Embryology - User contributions [en-gb]

User:Z3415242

2014-10-29T00:20:21Z

Z3415242: /* Lab Attendance */

==Lab Attendance==
Lab 1 --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:45, 6 August 2014 (EST)

http://www.ncbi.nlm.nih.gov/pubmed

[http://www.ncbi.nlm.nih.gov/pubmed Pubmed]

[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID2508416]

<pubmed>25084016</pubmed>

Lab 2 attendance --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:25, 13 August 2014 (EST)

Lab 3 attendance -- --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:12, 2 September 2014 (EST)

Lab 4 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:31, 27 August 2014 (EST)

Lab 5 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:53, 3 September 2014 (EST)--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:53, 3 September 2014 (EST)

Lab 6 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:41, 10 September 2014 (EST)

Lab 7 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 11:24, 17 September 2014 (EST)

Lab 8 attendance----[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:48, 24 September 2014 (EST)

Lab 9 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 12:19, 8 October 2014 (EST)

Lab 10 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 11:43, 15 October 2014 (EST)

Lab 11 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 15:13, 22 October 2014 (EST)

Lab 12 attendance--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 11:20, 29 October 2014 (EST)

==Lab Assessment 1==

===Article 1===

<pubmed>PMC3985938</pubmed>

The above article has suggested that vitamin D may have an impact on human reproduction. The aim of the investigation was to see if vitamin D levels can help predict rate of implantation and clinical pregnancy in infertile women after having IVF (in vitro fertilisation).

Method

The following method was used to perform the investigation. Vitamin D status as determined by serum 25(Oh) D levels were evaluated amongst a group of woman who went for IVF. 182 women were recruited and of that 172 were included for analysis. Woman who were aged 18-41 years, had FSH level 12 IU/L or lower and were able to provide informed consent were included in the study. Third party reproduction cycle, those with uterine abnormalities and language barriers were excluded. The participants underwent a normal IVF cycle. Standard agonist and antagonist protocols were used. Busrelin acetate was used in the agonist protocol and cetrolix acetate or ganirelix acetate was used in antagonist protocol. Controlled ovarian hyper-stimulation was achieved by recombinant or purified FSH with or without LH or human menopausal gonadotropin. The doses of the medication were determined on individual basis.

Ovarian response was examined by serial transvaginal ultrasonography as well as through serum lutenizing and estradiol assay. Serum25 (OH) D samples had been collected before oocytes were retrieved. Nuclear maturation was triggered with HcG.Oocytes were retrieved under ultrasound guidance transverginally 36-38 hours following injection of HCG. On day 3-5 after fertilisation, embryo was transferred and vaginal progesterone was used for luteal phase support.

Findings

Patients were classified into sufficient (greater than 75nmol/L of vitamin D) and insufficient levels(less than 75nmol/L). From results, those from sufficient group showed to be more likely to undergo embryo transfer on day 5( 71.8% as statistically analysed) compared to woman from insufficient group ( 58.9%). Higher clinical pregnancy rate per cycle was discovered amongst woman with sufficient level compare to woman with insufficient level. They also found higher clinical pregnancy per embryo transfer in the sufficient group of woman. Implantation rate was observed to be higher in sufficient group however this was not statistically significant. Multivariable analysis adjusted for age, BMI and day 5 verses day 3 embryo transfers showed that serum level was an independent predictor of clinical pregnancy. Woman in this study with sufficient vitamin D level had a higher rate of clinical pregnancy following IVF compare with woman with insufficient level. Vitamin D supplement could provide an easy and cost effective way of improving pregnancy rate in woman undergoing IVF.

===Article 2===

<pubmed>24834703</pubmed>
Properties of Zona Pellucida are believed to be important for oocyte cytoplasmic maturation and meiotic spindle for chromosomal alignment and proper separation of maternal chromosome. This study aimed to find the possible effect of ZP birefringment properties and mitotic spindle visualisation and localisation as a predictor of IVF outcome.

Method

This was a perspective study performed over 16 months at Medical University of Bialystok Poland where 51 patients undergoing IVF-ET (In vitro fertilisation and embryo transfer), intracytoplasmic sperm injection (ICSI) were included. Of 51 couples 39 had unexplained infertility and 12 had mild male factor. Two different methods for controlled ovarian hyper stimulation were used.

1. Long protocol (n=32) – The drug used was GNRH agonist Diphereline SR. It is a recombinant form of FSH.

2. Antagonist protocol (n=19). FSH and GNRH antagonist was used.

Ovulation was induced with HCG (human chorionic gonadotropin) in all patients. Oocyte retrieved transvaginally under ultrasound guidance 36 hours after HCG injection. Oocyte denudation was performed using hyaluronidase. Before intracytoplasmic sperm injection (ICSI) non invasive measuring with Olympus X7 inverted microscope was performed. Through this 228 cumulus oophorus were selected to be examined. 31were excluded due to inadequate oocyte maturation. Examination was done in different ways. 1. ZP birefringence was evaluated in a scale of 0degree to 4degree, 2. ZP autoscoring was performed, 3. ZP numeral autoscoring was performed, 4.MS visualisation, 5.Spindle detection and localisation of MS in relation to polar body.

Detection was grouped as:
1. Oocyte with spindle forming at less than 30 degree
2. 30-45 degree 3. 45-120 degree and
4. More than 120 degree, to PB. Oocytes whose spindles were located to be in another position where rotated in such way that the injected needle did not penetrate it.
After this, oocytes were able to be divided into 3 groups. Group1: Embryo selected for transfer and outcome- day 14 after ET positive pregnancy test. Group 2: Embryo selected-day 14 after ET negative pregnancy test, Group 3: Embryo was not selected for transfer.

FINDINGS

Autoscores obtained in all three groups were nearly identical and no statistically difference were found in study groups. MS localisation in relation to PB was very close ( <450) in 70.9% of oocytes. The rate of MS positive oocyte was highest in group with pregnancy but statistically not significant. Between oocyte selected and non-selected for ET, no statistically significant difference is numeral score of ZP was found. ZP manual evaluation indicated stronger bifringement when pregnancy was not achieved. The rate of MS positive oocyte was higher in group with pregnancy. None of this was statistically significant so it was concluded that polarisation microscopy imaging and rating of ZP and MS cannot be a direct predictor of IVF outcome.

--[[User:Z8600021|Mark Hill]] These articles are good for fertilisation. (5/5)

==Lab Online Assessment 2-IMAGE==

[[File:Journal.pone.0027635.g002.png|300x500px|framed|center|Adriamycin treated mouse shows association of abnormal notochord branching and fore gut abnormality]]

'''A)'''Different angle of a control embryo showing endoderm, notochord and floor plate in white. '''(B-H)'''- Adriamycin treated embryos immunostained for HNF3β demonstrating morphological abnormalities. Abnormal notochord branching is indicated with red arrow while different fore gut abnormalities are indicated with green arrow.<ref><pubmed>0027635</pubmed>|http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027635]</ref>

<references/>

Copyright: © 2011 Hajduk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

{{Template:Student Image}}

--[[User:Z8600021|Mark Hill]] You needed to have remained the image file with a name identifying what it is showing, also include the reference, copyright and student template here as well as on your student page. This is so the information is always associated with the file itself no matter where it is used. You do not need to put the student template here on your page only with the file. (3/5)

==Lab Online Assessment 3==

Subheading:

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>
2.<pubmed>3832654</pubmed>
3.<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

<references/>

--[[User:Z8600021|Mark Hill]] These are appropriate references, I do not understand why you have formatted reference 3 differently? (4/5)

==Lab Online Assessment 4==

'''1. Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''

''Successful Stem Cell Therapy Using Umbilical Cord Blood-Derived Multipotent Stem Cells for Buerger's Disease and Ischemic Limb Disease Animal Model''

The study found a possibility of treating Buerger’s disease patients by using MSC ( Mesenchymal stem cells) that came from human umbilical cord blood(UCB). Results supported the theory of angiogenesis as being a therapeutic mechanism used by UCB derived MSC in patients with Buerger’s disease.

Through Angiography, it was discovered that in affected lesion, there was an increase in capillary formation and decrease vascular resistance when UCB derived MSC was transplanted to patients with Buerger’s disease. Furthermore ischemic rest pain reduced more rapidly (within 2 weeks) than the formation of new capillaries which took 120 days after the Angiography.

Buerger’s disease is not common in animals so femoral artery ligation was performed to induce limb ischemia in animals. This was followed by medium control and un-injected control. Limb salvage was not observed in either medium control or uninjected control. 1 day after femoral artery ligation, extensive forefoot necrosis was observed and this lead to spontaneous amputation in 70% (7 out of 10) in both controls. Preserved limb was observed in 3 out of 7 of uninjected control while in contrast, 5 out of 8 mice with UCB derived MSC transplant was associated with successful limb salvage. Foot necrosis was limited in only 4 of 8 with necrotic lesions being healed within a month and only 38% with UCB derived MSC transplant showed spontaneous limb amputation. So there was statistical significance between UCB derived MSC treated mice and medium and uninjected controls therefore showing that UCB derived MSC blood stem cells can have therapeutic use for Buerger’s disease.

''Reference:''

<pubmed>16497946</pubmed>

'''2.There are a number of developmental vascular "shunts" present in the embryo, that are closed postnatally. Identify these shunts and their anatomical location.'''

'''Ductus Venosus:''' It is a temporary blood vessel (fetal vein) carrying oxygenated blood. It bypasses through the fetal liver, originating at the left umbilical vein (at the placenta) and going to the inferior vena cava to the heart of the fetus.

'''Ductus Arteriosus:''' is a blood vessel in the developing fetus which lies between the left pulmonary artery and the proximal descending aorta of the fetus and thus connecting them. It bypasses the lung to distribute oxygen which is received through the placenta from the mother’s blood.

'''Foramen Ovale:''' is an opening located between two atria which bypasses the lung to allow blood to be channelled in the systemic circulation. Blood enters the right atrium then through foramen ovale and into the left atrium.

==Lab Online Assessment 5==

'''Laryngeal Atresia'''

The larynx develops from endodermal lining and the adjacent mesenchyme of the foregut between 4th and 6th Branchial arches. The foregut is first identifiable at 20 days gestation and ventral laryngotracheal groove differentiates into primitive laryngeal sulcus by 22 days and right and left lung buds appear by 24 days.[1]The laryngotracheal groove continues to deepen until its lateral edges fuse.

The failure of recanalisation of the laryngotracheal tube and therefore the non-development of the 6th brachial arch during embryological development causes Laryngeal atresia, a type of congenital high airway obstruction syndrome which is usually fatal. This rare anomaly occurs during the 3rd month of gestation and the larynx remains blocked by cartilage and other tissue and therefore there is complete absence of lumen in a new born baby.[1] There have been reported of 50 reported cases of larynx atresia in world literature.

Laryngeal atresia may be associated with other genetic abnormalities such as left persistent superior vena cava, single umbilical artery, oesophageal atresia and renal agenesis. [2] Partial trisomy 9 and 16, chromosome 5p deletion and 22q11.2 were also suggested as associated causes of Laryngeal atresia. [2]

'''Reference:'''

[1].<ref>Tewfik T.L.,Meyers A.D.,2013,July,Congenital Laryngeal Atresia, Cysts, and Lymphangioma, Medscape, [ONLINE] Available at:http://emedicine.medscape.com/article/837630-overview</ref>

<references/>

[2]. <pubmed>3566610</pubmed>

==LAB 7==

'''Identify and write a brief description of the findings of a recent research paper on development of one of the endocrine organs covered in today's practical.'''

The study was to investigate the role of Hes1 in thyroid development. The Hes1 expression was measured during Thyroid differentiation. Thyroid development in mice lacking in Hes1 was also studied. During normal mice thyroid development, Hes1 was detected from E9.5 onwards. The findings revealed dual role of Hes1 during Thyroid development, first-control of number of both thyrocyte and C-cell progenitors (via p57-independent mechanism) and second-adequate differentiation and endocrine function of thyrocytes and C-cells. Mice with Hes1 mutation showed severe thyroid hypoplasia and also decreased production of T4 and calcitonin. Results also suggested Hes1 expression was required for the developing thyroid gland to reach its normal size and shape.

<pubmed>PMC3045378</pubmed>

'''Identify the embryonic layers and tissues that contribute to the developing teeth.'''

Two types of teeth develop. Deciduous teeth and permanent teeth. Teeth develop from oral ectoderm, mesenchyme and neural crest cells. The tooth enamel is derived from the ectoderm of the oral cavity while the rest of the tissues differentiate from neural crest cells and mesenchyme. Tooth development involves induction between neural crest mesenchyme and oral epithelium.

==Lab 8 Online Assessment==

'''1.Provide a brief time course and overview of embryonic development of either the human testis or ovary. (2-3 paragraphs) '''

The primitive sex cells are developed in 4th week by proliferation of endodermal cells of dorsal wall of hindgut. The primordial germ cells appear beneath the surface epithelium of genital ridge after dorsal migration from endodermal wall of hindgut. During later part of 5th week, sex cells reach genital ridge. First sex cords containing germ cells projects from surface epithelium to the medulla of the genital ridge, this forms “rete ovarii”. <ref name="PMID24741072"><pubmed>24741072</pubmed></ref>The medullary sex cords regresses to form vascular and replaced by vascular stroma. When sex cells appear in cortex, medulla regresses and cortex is converted into the ovary. <ref name="PMID24741072"><pubmed>24741072</pubmed></ref>

In the embryo, Chromosomal sex directs the development of ovaries. Initially, undifferentiated gonad contain product of WNT4 and SOX9 genes. Usually SOX9 inhibit the function of WNT4, in absence of SRY genes the function of SOx9 is withdrawn therefore uninhibited WNT4 responsible for formation of ovary from cortex of undifferentiated gonadal ridge. <ref name="PMID 25246082 "><pubmed>25246082</pubmed></ref> The gonadal sex becomes apparent in ovaries in 8th or 9th week. The absence of Y chromosome results in the development of female phenotype, with or without formation of ovary

Each ovary is developed from the cortex of the undifferentiated genital ridge. The second generation of sex cords develops from the surface epithelium to the cortex. The sex cords are broken into different fragments and each fragmented mass forms the primary ovarian follicle and contain oogonium. Oogonium is surrounded by follicular cells which are derived from mesenchyme or sex cords. The surface epithelium of the ovary is thick and undergo proliferation and so it is known as germinal epithelium. At birth each ovary contain about 2.5 million primary follicles. Most follicles degenerate and are replaced by interstitial cells. Only few un-encapsulated sex cells undergo successive maturation in each menstrual cycle. <ref name="PMID20111701"><pubmed>20111701</pubmed></ref>

The ovary develops only from the middle part of the genital ridge. The cephalic part of the genital ridge forms suspensory ligament of the ovary and the caudal part incorporates with gubernaculum. The primitive ovary lies retro-peritoneally of the dorsal abdominal wall. The gubernaculum of ovary is an intermediate attachment to developing uterus which drags the ovary into the pelvis. <ref name="PMID24741072"><pubmed>24741072</pubmed></ref>The proximal part of gubernaculum forms ligament ovary and distal part forms round ligament of uterus.

<references/>

'''2. Include an image from the historic genital embryology section of the online notes in your description.'''

'''
[[File:Bailey329.jpg|500px]]

'''Transverse section of the ovary of a fox embryo.''' Primitive ova seen as the large clear cells

==Lab 9 Online Assessment ==

Group1

The group has provided a well summarised introduction of the respiratory system including its main function and the main anatomical features of it (conducting zone, respiratory zone) explanation was easy to understand. They have also explained the two stages (embryonic and fetal) and explained one of the key events that occur in the fetal stage Not only that but there is further information of what happens after fetal stage as its’ development continuous postnatal. In addition there is diagram to help aid in visualising these anatomical features and how it looks as it develop, however there is no labels in the diagram and so readers are unable to understanding its significance nor visualise correctly. Some of the diagrams are randomly pasted into the site with no explanation or context.

There is good choice of subheading clearly stating what it will be talking about and the use of a table to illustrate the fetal stage in development of the respiratory system is well put. It makes it easy to understand and summarises the key fetal stage events, allowing reader to easily orientate at what time frame, a particular feature is developing into. Research findings are relevant to the topic and recent, having it in short paragraph helped in understanding what was found from the research articles however some of the findings seemed incomplete towards the end, a bit more information could be added and there is information about a proposed model under the recent research heading, this could be misleading to the reader. Historic finding is well written its clear, to the point and correct headings have been used. Good use of time dates (shows research) and historic drawings are simple and relevant to the information given besides them.

There is an adequate amount of abnormalities with main ones explaining who it affects and problems associated with it. One of the abnormality is not defined however rest shows research has been done and good use of image, shows it in real life context. Overall the project has shown research has been done especially in historic findings and abnormalities. Some of the information in the introduction has not been citied however the information that has been is correctly citied (including the pictures). To make it look neater I would suggest having reference as a 1 whole list at the bottom of the page. Good use of the table

Group 2

This group has put appropriate subheadings which follow the learning aim of embryology. Introduction is not to long could cut down on the physiology of the renal system and put more in its anatomical features and its development in fetal stage, also like how they introduced abnormalities in the introduction. There is no historic finding and I would suggest the historic findings being underneath the timeline heading. There is a basic timeline which is good as it helps clearing and understanding the key event occurring at a particular time frame. Good integration of recent finding and model and image was relevant and easy to interpret. Could include a bit more recent research.

The development of each component of the renal system is well structured. Each structure involved in the renal system is clearly shown as a heading. For kidney it is good there is a brief outline of what happens in the embryonic stage as kidney’s and then more detail explanation of development of the different parts of the kidney in the fetal stage. It helps readers to understand the basic start of kidney development to then understand how it grows form there in the fetal stage. Urethra and Bladder is well explained clear and concise, it shows research has been done while Ureter needs more work put into it, it looks incomplete and reader is left unsure of when the event are occurring.

Overall a well orientated project referencing is in correct format there is just some error with the reference under the Ureter heading which needs to be fixed ( have same format as the rest of the group project). Images used were excellent as there was a variety of historic picture, simple drawings and labelled diagrams. They were correctly referenced and labelled helping showing a good understanding of the topic and helping teach readers. For variety could possibly use a table for timeline and maybe video.

Group 4

There are key points relating to the topic shown in table format and bullet points. The table is well used for the timeline of events occurring in both female and male and provides simplicity however it looks incomplete and disorganise. Majority of the table shows embryonic stage and female development looks incomplete. Under the timeline there is a paragraph introducing the genital system development, it does not fit there and does not flow with the information given in the timeline above. There is also diagram placed below it with which is not labelled however it is relevant and good as it provides an overview of how the two different genitals develop.

Current research and model heading has some relevant information such as what signalling and growth factor could affect the system in development as well as showing mouse models being used however there is some irrelevant information that doesn’t clearly show what model is being used such as that under the “Female” heading. It looks like they have just stated the event occurring in the development. There isn’t much research shown in this section.

Historic findings is well researched for male genital system. It’s clear and shows events occurring in chronological order. Appropriate information is used and it’s highly detailed for testicular descent and prostate formation however some information is not citied. A picture or video could be included in this section to make it more understandable and engaging. The female historic finding does not have a time frame into when in history theories of its formation occurred. There is also no subheading like that of male system to make it clear and distinct. Diagram of mullerian duct is good and relevant just needs clearer information about vagina formation and ovary, possibly could include a diagram of either vagina, uterus or ovary formation.

Abnormality section is well written, it is organised appropriately by first discussing male abnormality and then female abnormality and then both. It clearly defines the abnormality and there is a range of picture that relate with the information given used (hand drawn and labelled diagram).

Overall the headings in this project page are related to the objects of the assignment, some good use of drawings and diagram however they need to be better organised (such as the very first diagram) and some are not properly labelled which needs to be fixed. Group has also shown a relevant video of development of reproductive system however it looks out of place on the page needs to be placed somewhere better. The research model section has some key points relating to their topic however some section talks too much of embryonic period which not relevant to the project. More pictures could be added into this section and information could be better organised instead of having list of points where some don’t relate with the point above it. Citation and reference is correctly done however having a list throughout the page and also at the end makes it look disorganised. Having in one section would make it neater and easier for readers to navigate.

Group 5

The page is well organised, key points relating to topic is clearly described in the “development overview section”. Not only do they put in dot point keeping it short and to the point there is also table and diagrams appropriately used to enhance understanding of development of skin in fetal stage. It shows they have understood the topic. Particular liked the teeth table as it showed good understanding of the phase in its development and it was clear and to the point. Hair section could be written in dot point just to have consistency with rest of information and the diagram in gland section could be placed on the opposite side, it disorganise the information when placed in the middle. Overall good overview nail section could include picture.

Recent findings although incomplete there is good research provided on skin and hair follicle. There should be 1 or 2 more research findings included for either for nail or gland however with what it written on the page it is relevant and in-depth. Could put it in dot points so that readers don’t lose interest in reading the whole thing and also so it’s easier to understand. Diagram is labelled and relates to the second recent finding information showing sufficient level of research. Although mentioned mouse model there is no other models mentioned for any of the Integumentary development, should make a subheading for it and try including 2-3 models.

In historic findings the hair section is well written shows good understanding and appropriate subheadings have been used (structure, Development). Its in chronological order and key points have been addressed, other structures doesn’t show enough research being done its basic and incomplete for example Skin. In this section some labelled diagram would make it more engaging to read.

Abnormalities is well written it is clear and they are all defined with real life pictures associated with the abnormalities making it easier to visualise. Thorough research is evident in this section and it is of appropriate length. Overall the project page is well organised and quite engaging having table format, historic pictures as well as real life picture and even adding colour to the page. Could maybe include video onto the page. Reference is in the correct format and it’s good that there is list at the end of the page, maybe for consistency just have reference at the end instead of both (throughout the page and at the end). Recent findings could be simplified further while more information could be added for recent model and for historic findings for some structures.

Group 6

The page is well formatted in terms with heading and choice of content such as diagrams, tables and graphs. Having the different organs as headings is good as it allows the readers to take in information in a logical manner. It is good that timeline is included under each organ heading shows understanding of the whole endocrine system by breaking it down organ by organ however each sections is not consistent with the other one. Some has development overview while others write timeline I would suggest to keep it as same heading for all. There is good description of each organ at the beginning of each section and in the timeline there is key events described showing understanding and helping to learn.

All sections are incomplete in some form or another. The diagram used are good and relevant especially the pancreas cells diagram. It is well explained and shoes evidence of research. Pineal gland timeline looks incomplete or doesn’t show evidence of enough research however the recent finding is relevant and good in this section, other sections have not included recent finding showing some lack of research. Other sections also have incomplete tables and could put diagrams or drawings to so information can be better understood for readers. A video or two could also be added on the page and a section for historic finding should be added under each headings.

Overall there is some good information that shows evidence of research in the development of the different endocrine organs however there is lack of models and research findings as well as historic findings, even abnormalities are not well explained in each headings. It is not easy to navigate as each headings are not consistent with each other however the diagrams used are relevant and properly explained and citied. There is also good use of table to enhance understanding of hormones involved and with few adjustments page will look organised and be logical to read. Reference is done correctly however it would make it more engaging and easier to follow if in text reference was done and having a list of the reference at the end. A short paragraph in the introduction would also help readers understand exactly what is involved in endocrine system.

Group 7

The introduction clearly divides the system in two parts and then provides a good brief overview of the CNS, which is relating to the topic as it helps to clearly understand the anatomical component of CNS system. Good brief description of embryonic stage so that readers can understand the later fetal stage. The diagram used is relevant in the introduction section and correctly citied however it could be a bit overwhelming maybe have a brief explanation of it underneath explaining what is happening the right hand bottom corner of it. There is evidence of understanding shown through the timeline of brain development which is shown in various form (table format and diagram). Diagram is labelled correctly and is relevant to chosen topic and it’s clear and simple to understand which is good. Timeline in the table format is well organised and brief with key points provided helping understand the basic of what happens during fetal development. Spinal cord development needs work done for it as well as Meninges Development. There is just heading having a timeline would be a good start and adding a picture or two to it.

There is evidence of research done through the current findings and model headings some good relevant links are shown however a lot are not summarised (just links). For the ones that are the first current research was well summarised others could have added a bit more information about the findings into it. In this section pictures would also be good to help understand and engage readers. Abnormalities section is started off well. There is relevant information of how common it is and good definition with a variety of picture shown besides it. The pictures are correctly labelled and cited and clearly illustrate the abnormality. For the rest there is need of a short summary of the abnormality however in the section there is evidence of research done as a variety of abnormalities have been listed or explained. Referencing is done correctly throughout the page however the links in the research models section could be placed at the bottom of the page once information from them are written.

Overall there is some good use of tables and diagrams. There is a variety of pictures used ranging from simple anatomical diagrams, x-rays and molecular pictures relevant to the topic. There is evidence of research done in certain sections and it is correctly formatted and appropriately set up with relevant headings in logical order. The information is not overwhelming and quite easy to follow. All images are correctly labelled the page is just incomplete in certain section however what is shown so far is relevant shows understanding and is easy to follow.

Group 8

The page is disorganised in certain aspects. The first heading is not appropriate and is not teaching at peer level. Timeline is incomplete could have phases (first trimester, second trimester etc.) and key events put into a table and shown.

There’s good information about the muscle development from myofiber to tubules etc. however there is no period of time given to when the event occurs so it can get confusing maybe include the week in the information. Molecular and cellular regulation is well described but some information such as how IFG1 has found to enhance protein synthesis could be put into a different heading specific on research findings. Tendon development is much clearer and easier to understand as it to the point and tells it as a series of event. Could include when the process ends only has shown that it started in 20th Carnegie stage

Second and Third trimester information is incomplete although the summary in second Trimester heading is easy to understand it can be expanded upon. Does anything happen to limb buds in fetal stage maybe could include information of muscles in that. The one Abnormality given is relevant and well summarised. It has been defined and shows how common it is which is good to include. There should be more abnormalities added into this section and possibly picture or diagram helping to visualise how it may look.

Referencing is done in the correct format and it’s good everything is shown as a list on the bottom of the page. Overall the page needs improvement there is some evident of research done however there needs to be more headings added such as Historic findings. The recent finding heading could be placed more up on the page, before abnormality heading. Can have the different trimesters as subheading instead of separate headings. Can include a timeline in table format and also some diagrams or pictures of muscle development in head region and tendon development as well as possibly a video. Good background of embryonic development but since embryonic development is not related the project can summarise it a bit more and add more into fetal development of muscles.

== Online Assessment LAB 10 ==

Method

Specific Cre mouse line, WNT-Cre and PO-cre were selected. These expressed Cre in a manner specific to Neural crest and thus these two Cre mouse lines were used to study NC derivation in developing tongue.

Four bitransgenic mouse strains Wnt1-Cre/R26R or Wnt1-Cre/ZEG and P0-Cre/R26R or P0-Cre/ZEG were generated as two Cre mouse line was bred with two report lines R26R lacZ reporter and ZEG(lacZ/EGFP) double reporter. By using PCR the mouse litter was then genotyped and the wild type littermates were used as negative controls of staining.
Embryonic and postnatal mice were used and were staged by vaginal plug detection. Tissues were then collected and the label cell distribution was then analysed. Analysis of Wnt1-Cre and P0-Cre labelled cell distributions was performed using sagittal sections of tongue. LacZ gene product β-galactosidase and EGFP labels were localised at different magnification by confocal microscopy.

Taste buds were divided into 3 groups fully, partially or not labelled after X-Gal staining. A fully labelled taste bud was without obvious X-Gal negative cell. Those with any X-Gal negative cells were partially labelled. From this quantity of taste buds were calculated in different part of the tongue.Using the mouse models there was thorough examination of Wnt1-Cre, on the location of NC-derived cells with R26R and ZEG reporter cells through different stage of developing tongue.

Finding

The tongue has taste sensory end organs, 3 types of papillae (circumvallate, foliate and fungiform as well as taste buds). From the study it was found that NC derived cells distribute within lingual epithelium and mesenchyme with close association with taste papillae in Wnt1-Cre and P0-Cre mice. There is new concept of the taste bud cells embryonic origin which includes NC derivation that the findings lead into. In P0-Cre/R26R mouse 95% of taste buds showed a significant contribution of NC derived cells to early taste bud development.

Wnt1-Cre and P0-Cre labelled NC-derived cells were both found to be in lingual epithelium and early developing taste buds of the tongue although not in the same proportions. Most taste buds showed P0-Cre labelled cell and as these cells were double labelled by taste marker it confirmed that they were taste cells. It was therefore found that fungiform taste bud cells obtained NC during taste development. Study also found Wnt1-Cre labeled NC-derived cells when GFP labelled were seen in taste papillae and lingual epithelium and thus had strong association with embryonic and early postnatal developing taste papillae.

The results suggest the NC derivation of taste organs. The NC cells around the neural tube migrate in early embryonic stage. Migrated NC cell in the epithelium and mesenchyme of the tongue undergo proliferation and differentiation to achieve taste papillae.

<pubmed>22659543</pubmed>

https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_-_Taste_Development#Taste_Buds

2014 Group Project 3

2014-10-24T08:32:14Z

Z3415242:

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring proof for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. <ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1810 || Kieser defended Oken’s propositions. He published a model of the intestine at 3 months showing his finding that coils of the intestine were lodged in umbilical cord rather than the abdominal cavity.<ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate organisms <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus <ref name="PMID25305782"><pubmed>25305782</pubmed></ref>
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T07:26:42Z

Z3415242:

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring proof for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. <ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1810 || Kieser defended Oken’s propositions. He published a model of the intestine at 3 months showing his finding that coils of the intestine were lodged in umbilical cord rather than the abdominal cavity.<ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus <ref name="PMID25305782"><pubmed>25305782</pubmed></ref>
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T07:04:40Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring proof for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. <ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1810 || Kieser,defended Oken’s propositions. He published a model of the intestine at 3 months showing his finding that coils of the intestine were lodged in umbilical cord rather than the abdominal cavity.<ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus <ref name="PMID25305782"><pubmed>25305782</pubmed></ref>
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T07:01:45Z

Z3415242: /* Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring proof for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. <ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1810 || Kieser,defended Oken’s propositions. He published a model of the intestine at 3 months showing his finding that coils of the intestine were lodged in umbilical cord rather than the abdominal cavity.<ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:59:13Z

Z3415242: /* Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring prove for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. <ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1810 || Kieser,defended Oken’s propositions. He published a model of the intestine at 3 months showing his finding that coils of the intestine were lodged in umbilical cord rather than the abdominal cavity.<ref>Keibel,F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:47:25Z

Z3415242: /* Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring prove for following ideas:
1. The intestine did not lie in the abdominal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicus and enter abdominal cavity so the necessary umbilical hernia is present in embryos. Keibel, <ref>F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:44:26Z

Z3415242: /* Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1806||Oken believed the embryo was nourished through umbilical vesicle. In this year he published treatise, declaring prove for following ideas:
1. The intestine did not lie in the abdorminal cavity originally but came from the vesicle (vesicular umbilicus) which was outside amnion.

2. Duodenum is prolongation of the stomach in which it splits into anterior and posterior intestine which go into abdominal cavity.

3. After intestine has no continuity and angular splicing with a valve, it begins to draw backwards to the umbilicius and enter abdominal cavity so the necessary umbilical hernia is present in embryos. Keibel, <ref>F. and Mall, F.P. J. B. Lippincott Company, Philadelphia (1912)</ref>

|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:11:49Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===
[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:06:24Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|left|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T06:02:21Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T05:53:28Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|right|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T05:46:50Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

[[File:Thymosin B4 detection in foetal developing ileum.jpg|thumb|left|250px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T05:33:45Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1802-33 || contributions by Johann Friedrich Meckel to the study of the abnormalities occurring during the embryological development. Earning Meckel's diverticulum among other structures to be named after him <ref>J. F. Meckel: Über die Divertikel am Darmkanal. Archiv für die Physiologie, Halle, 1809, 9: 421-453.</ref>
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube. <ref name="PMID25286746"><pubmed>25286746</pubmed></ref>
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus <ref name="PMID"25197202 ><pubmed>25197202 </pubmed></ref>
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

File:Malrotation.jpg

2014-10-24T05:15:30Z

Z3415242:

File:Malrotation.jpg

2014-10-24T05:14:51Z

Z3415242:

==Image of malrotation of the midgut colon and ileum==

This image shows that the cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.

==Reference==
<ref name="PMID24963436"><pubmed>24963436</pubmed></ref>
<references/>

==Copyright==

Copyright © 2014 Huseyin Kazim Bektasoglu et al.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

-----
Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.

{{Template:Student Image}}

File:GIT 2.jpg

2014-10-24T05:08:49Z

Z3415242:

==Large Omphalocele in fetal development==
the image shows large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.

==Reference==
Image adapted from:
<ref>{{O'Toole, M. (2003). Miller-Keane encyclopedia & dictionary of medicine, nursing & allied health. Philadelphia, Pa.: W. B. Saunders.}}</ref>

<references/>

==Copyright==

Beginning six months after publication, I z3415242 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode

{{Template:Student Image}}

z3415242

File:Different forms of cleft palate.png

2014-10-24T05:04:31Z

Z3415242:

==Cleft palate during fetal development==
This image shows different types of cleft palate with A)Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.

==Reference==

Image adapted from:
Motifolio.com, (2014). Various types of cleft lip and cleft palate PPT PowerPoint drawing diagrams, templates, images, slides. [online] Available at: http://www.motifolio.com/1011245.html [Accessed 15 Oct. 2014].

==Copyright==

Beginning six months after publication, I z3415242 grant the public the non-exclusive right to copy, distribute, or display the Work under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/ and http://creativecommons.org/licenses/by-nc-sa/3.0/legalcode

COPYRIGHT STATEMENT

Hand drawn image

I, the copyright holder of this work, release this work into the public domain. This applies worldwide.
In some countries this may not be legally possible; if so:
I grant anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law.

------

{{Template:Student Image}}

2014 Group Project 3

2014-10-24T04:52:52Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1780 || The famous ''Dissertationi di fisica animale e vegetale'' by Lazzaro Spallanzani is published where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices. known now as The Chemical Theory of Digestion
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Rotations (Embryonic)===

Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID23516636"><pubmed>23516636</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T04:36:47Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID19884687 "><pubmed>19884687 </pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T04:23:02Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID23516636"><pubmed>23516636</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T04:15:54Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID24689077"><pubmed>24689077</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T04:08:04Z

Z3415242: /* GIT system Overview */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|200px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T04:04:07Z

Z3415242: /* GIT system Overview */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|250px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref> The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

2014 Group Project 3

2014-10-24T03:57:05Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|300px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week 6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

'''Week 8-12'''
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Circular Muscle in colon]
* [https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Intramural ganglia develop]

'''Week 11'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Taeniae Coli and Huastral Clefts begin to appear]

'''Week 12-15'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Longitudinal muscle in colon]

'''Week 20'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Colon_Development Villi formation complete]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

[[File:Fetal Colonic Inury Model Diagram.png|500px|thumb|right|Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>]]

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

'''Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)'''

[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]
In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===
{| class="wikitable"
|-
! Year !! Research and Findings
|-
| 1900 || Choronschitzky presents findings on the emergence of spleen, liver, gallbladder, pancreas in vertebrate systems <ref>CHORONSCHITZKY: Die Entstehung der Milz, Leber, Gallenblase, Bauchspeicheldruse und des Pfortadersyssems bei den verschiedenen Abteilungen der Wirbeltiere. Anat. Hefte, Bd. XIII, 1900.</ref>
|-
| 1900 || Berry J, M studied histological development of the small intestines where he noted that no evidence of villi by week 7 could be found. The villi could be observed in the duodenum by weeks 8-9 and along entire length of the small intestines by week 12

|-
| 1914 || Johnson F, P made detailed descriptions on the early development of the anal canal and postulated that that an exact histological determination of the border between entoderm and ectoderm is impossible <ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

|-
| 1970 || Pace clears controversy on the age of appearance of the haustra within the human colon, showing Taeniae Coli and Huastral Clefts in week 11 of development<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

|}

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
[[File:Human- fetal week 10 sagittal plane D.jpg|300px|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

[[File:Week 10 Midgut Herniation.png|500px|thumb|left|Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
[[File:Week 11 Midgut Herniation.png|500px|thumb|right|Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>]]
'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca.<ref name="PMID12740945"><pubmed>12740945</pubmed></ref> By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.<ref name="PMID17853405"><pubmed>17853405</pubmed></ref>

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery.<ref name="PMID20563874"><pubmed>20563874</pubmed></ref>

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

'''Anorectal deformities'''

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

''Cloacal Extrophy''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:Cloacal_extrophy.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

''Deep deformities:''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

==References==
<references/>

File:Different forms of cleft palate.png

2014-10-24T03:54:05Z

Z3415242:

Different types of cleft palate with A)Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.

-NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.

Reference
-----------
Image adapted from
Motifolio.com, (2014). Various types of cleft lip and cleft palate PPT PowerPoint drawing diagrams, templates, images, slides. [online] Available at: http://www.motifolio.com/1011245.html [Accessed 15 Oct. 2014].

Copyright
----------

COPYRIGHT STATEMENT

Hand drawn image

I, the copyright holder of this work, release this work into the public domain. This applies worldwide.
In some countries this may not be legally possible; if so:
I grant anyone the right to use this work for any purpose, without any conditions, unless such conditions are required by law.

------

{{Template:Student Image}}

File:GIT 2.jpg

2014-10-24T03:44:46Z

Z3415242:

Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.

Reference
-------

Image adapted from
<ref>{{O'Toole, M. (2003). Miller-Keane encyclopedia & dictionary of medicine, nursing & allied health. Philadelphia, Pa.: W. B. Saunders.}}</ref>

<references/>

Copyright
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Hand drawn image

{{Template:Student Image}}

2014 Group Project 3

2014-10-23T22:52:11Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|300px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

Recent Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|frame|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

''For this section some references were from the Moore, KL, Persuad, TVN & Trochia MG. (2011) '''The Developing Human: Clinically Oriented Embryology''' (9th edition). Philadelphia: Saunders''

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T22:41:55Z

Z3415242:

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==
[[File:Adult gastrointestinal tract cartoon.jpg|thumb|right|300px| Grown GIT system.]]
The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

Recent Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T22:37:00Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

Recent Findings on Omphalocele: (Sonic hedgehog expression in the development of hindgut)

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T22:34:06Z

Z3415242: /* Current Research, Models and Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T16:18:33Z

Z3415242: /* Current Models */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation from embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T16:09:18Z

Z3415242: /* Current Research, Models and Historic Findings */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation form embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T16:02:59Z

Z3415242: /* Current Models */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation form embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes.<ref name="PMID20482879"><pubmed>20482879</pubmed></ref> The pancreas was the only organ that showed synthesize of serine proteinases (trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation. <ref name="PMID20482879"><pubmed>20482879</pubmed></ref>

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|}

|-bgcolor="E0 FF FF"
|
|}

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T15:47:49Z

Z3415242: /* Current Models */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

'''Xenopus.Laevis model system revealing molecular pathway of gut adaptation form embryo to adult'''

The gastrointestinal tract is remodeled from embryo to adult to adapt to changing dietary environment. To study the mammalian gastrointestinal development as well as to determine genes and signalling programs which are important for gut development and maturation the Xenopus.Laevis metamorphosis system became a great model system for use.

A change in gene expression during mammalian intestinal maturation and postembryonic development was observed by investigating similarities in gene regulation between X.Laevis and mouse. Both systems have increase T3 level which circulates in the blood stream during the postembryonic development therefore the study focused on genes whose expressions increased with more T3 levels. Genes were therefore ranked based upon their relative expression at stage 61 From this gene expression profiles, 6 major gene clusters which are involved in intestinal transformation from embryo to adult were identified. The two clusters of genes had peaks at around birth in mammals. The X.laevis model helped contribute in identifying novel embryonic and adult specific genes providing a better insight of the molecular regulation of GI development as well as its function. 17 embryonic specific and 52 adult specific genes were identified and showed relationship to the development and physiology of the organs of the GIT. For example in mature intestine there is significant increase of PRSS2 and PRSS3 enzymes. The pancreas was the only organ that showed synthesize of serine proteinases ( trypsins) during maturation. The comparative analysis showed that during mammalian intestinal development genes that peaked at stages 61 were significantly up-regulated at birth in mouse suggesting molecular signatures are highly conserved in more than one species during GI development and that T3 can have potential role of regulating target genes in intestinal development.
TGF-B signalling pathway was analysed used GenMAPP database and it was seen to have proliferating role in intestinal maturation and cell proliferation.

Overall the gene expression studying with the utilisation of X.Laevis system provided molecular description of maturation and remodelling of the postembryonic developing Gastro intestine improving understanding of intestinal organogenesis as well as the nature of molecular regulation during fetal development.

|-bgcolor="E0 FF FF"
|
|}

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===
[[File:Histology of human embryonic liver at 11 weeks.png|300px|thumb|right|Histology of human embryonic liver at 11 weeks]]
Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.
[[File:Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group.png|300px|thumb|right|Photomicrographs of gallbladder samples stained with hematoxylin and eosin in each group]]
The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T14:18:41Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

[[File:3–11_SS_caudal_foregut_endoderm.png|200px|thumb|right|3–11 SS caudal foregut endoderm]]
<ref name="PMID22815796"><pubmed>22815796</pubmed></ref>

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

[[File:Malrotation.jpg|thumb|right|200px| Reverse rotation: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.]]

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

File:Malrotation.jpg

2014-10-23T14:09:01Z

Z3415242:

cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.

<ref name="PMID24963436"><pubmed>24963436</pubmed></ref>
<references/>

Copyright © 2014 Huseyin Kazim Bektasoglu et al.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

-----
Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.

File:Malrotation.jpg

2014-10-23T14:07:18Z

Z3415242: cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side. <ref name="PMID24963436"><pubmed>24963436</pubmed></ref> Copyright © 2014 Huseyin Kazim Bektasoglu...

cecum ended up on left side labelled as black asterisk while ascending colon and terminal ileum shown as white asterisk is running to the right side.

<ref name="PMID24963436"><pubmed>24963436</pubmed></ref>

Copyright © 2014 Huseyin Kazim Bektasoglu et al.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

-----
Note - This image was originally uploaded as part of an undergraduate science student project and may contain inaccuracies in either description or acknowledgements. Students have been advised in writing concerning the reuse of content and may accidentally have misunderstood the original terms of use. If image reuse on this non-commercial educational site infringes your existing copyright, please contact the site editor for immediate removal.

2014 Group Project 3

2014-10-23T13:32:53Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|
|-
! Abnormality name !! Affected region!! phase of occurrence !! Definition
|-
| Esophageal atresia || Foregut (Esophagus) || occurs in 8th week || 1 in 3000-4500 birth- results from deviation of trachoesophageal septum and there is incomplete separation of the eosphagus from laryngotracheal tube.
|-
| Eosphageal stenosis || Foregut (Esophagus) || during week 8 || Due to incomplete recanalisation of Esophagus
|-
| Congenital hypertrophic pyloric stenosis ||Foregut (stomach) || onset at 3rd week and can present neonatally || 1 in 150 male and 1-750 female- muscular thickening of the pylorus
|-
| Anal agenesis || Hindgut || week 7 || Anal canal end blindly or ectopic anus, or anoperineal fistula. Anal canal may open into vagina in female or urethra in male.

<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T12:40:18Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowel is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as there are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T12:37:51Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16-20 the villi appear throughout the entire intestinal tract. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==
{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

'''Reverse rotation'''

Congenital abnormality of the Midgut seen in one of 5000 live births. Normally after the midgut has undergone retraction into the abdominal cavity it undergoes a 180 degree counterclockwise rotation at week 10-11. Reverse rotation is when this midgut loop rotates in clockwise direction instead. Doudenum lies anterior to the superior messentric artery ( normally it should lie posteriorly) and transverse colon lies posterior instead of anterior to it ( artery). <ref name="PMID">24963436<pubmed>24963436</pubmed></ref> It is crucial that an early diagnosis is done as their are life threatening complications associated with it.

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T11:37:49Z

Z3415242: /* GIT system Overview */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production.<ref name="PMID9551687"><pubmed>9551687</pubmed></ref> The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T11:28:57Z

Z3415242: /* Abnormalities */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production. The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis. <ref name="PMID23554304"><pubmed>23554304</pubmed></ref>
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

2014 Group Project 3

2014-10-23T11:22:29Z

Z3415242: /* GIT system Overview */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production. The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. <ref name="PMID14745932"><pubmed>14745932</pubmed></ref> At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 5'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Duodenum Lumen of the duodenum becomes progressively small and occludes]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

'''Week 16'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Pancreas Insulin secretion begins by pancreas]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis.
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

<pubmed>4075420<pubmed/>

<pubmed>23553304<pubmed/>

<pubmed>2960962<pubmed/>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

File:Different forms of cleft palate.png

2014-10-23T10:22:48Z

Z3415242:

A)Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.

-NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.

Reference
Motifolio.com, (2014). Various types of cleft lip and cleft palate PPT PowerPoint drawing diagrams, templates, images, slides. [online] Available at: http://www.motifolio.com/1011245.html [Accessed 15 Oct. 2014].

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2014 Group Project 3

2014-10-23T10:02:26Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production. The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|270px|A)Fetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis.
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

<pubmed>4075420<pubmed/>

<pubmed>23553304<pubmed/>

<pubmed>2960962<pubmed/>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

Talk:2014 Group Project 3

2014-10-23T09:59:55Z

Z3415242: /* Discussion */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
{| class="wikitable mw-collapsible mw-collapsed"
! Reviews
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| A nice overview is presented for basic information to be presented onto the project page, with a descriptive introduction into the topic of GIT. Perhaps this section could include a brief mention of the aims of the page and perhaps a few images to make it more visually appealing. Timeline section is particularly extensive, however perhaps the layout can be altered- either adding further information to each developmental stage or even using a table format with images to aid the readers understanding of the processes. The subheadings of this section were also a particularly nice way to structure the information. Recent findings needs a bit more work- perhaps a particular focus could be established for this section of even links to a few articles organised by research into particular organs of the GIT. A few images would also increase the visual appeal to this section. The main body of information (foregut, midgut and hind-gut) are well covered and written- there is evidence of extensive research and work put into this section. The hand drawing idea was also particularly a good idea also with a proper description added to the image. Formatting to this section could be a little more unified however as some section use different styles of bullet points and ways to present the information. Deformities section is greatly informative; perhaps a few more should be presented with accompanying images. The overall references section was formatted correctly.

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*References are missing from the overview section. Although it serves as an introduction, you can still include references to support what you're saying. Also, maybe the language of this section should be edited to be a bit more formal, like the 2nd sentence in particular
*GIT = Gastrointestinal tract, not track
*The hyphens between "foregut" etc are not needed
*The timeline is a good idea! Everything was simplified. Maybe look to see if you can add some images to this section
*Week 6 of timeline: I don't think a liver can "obtain" a colour. Look to change the wording
*Maybe to simplify the timeline section better, tabulate the findings according to time (weeks), rather than dividing it by the midgut, foregut and hind gut section. It makes it hard to follow
*Need some more work on the recent findings section. Just some tips, when researching on pubmed, there's an option to look at recent articles by customising dates to say 2012-onwards
*Many potentials for adding images to the "foregut" section. If you find that copyright is too difficult to get around, then you can sketch or trace images from textbooks and upload them
*Great effort with the drawn images in the "midgut" section! Be wary of colour choice though, as the green highlighter and blue pen can be a bit difficult to see. Otherwise think of adjusting contrast on the images to make the diagram stand out more
*Maybe think of adding a video from YouTube to show some features of GIT fetal development, like the rotations. If you do that, be sure to include the 11-digit cache code as your reference point

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I think that the ‘Deformities’ section should be renamed to ‘Abnormalities’ and I am not sure if that is because it is the correct term but every lecture and similar page on the Embryology wiki uses the term ‘abnormality’ to describe abnormal developments. The page also needs to be more referenced more in some areas (e.g. the possible causes of Gastroschisis section) so as to allow your audience to read more into the text you have presented and give some citations to your information. Some sections are also suffering from a lack of information (e.g. ‘Recent Findings’ – more articles and ‘Abnormalities’ – more abnormalities) and I think some more research would definitely rectify these weak points.

I really liked the use of your own drawings in some of the sections and I think this demonstrates that you understand the concepts. My only criticism is that the images are a bit difficult to interpret because the colours are really hard to see against a white background. It would be good if you included some images from scientific literature as well to give more links to scientific papers.

Overall the page needs some more work and I think some more research and referencing will definitely go a long way in making this page better. You have the basic scaffold for you page and you only really need to develop some more detail in these areas.

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Your introduction to the gastrointestinal system provided a clear overview of what your project is about. I think it would be a good idea to couple this introduction with an image that shows the pathway and divisions of the GIT. The timeline shown is fantastic, it is not only extensive, but it divides the GIT into regions of the foregut, midgut and hindgut as well as the weeks in which key development events take place. It is in simple, easy to read language, at an element of teaching at the peer level- great work! There is also a reference next to each of these events which reflects the amount of research that took place-well done guys!

Your page includes a table with statistics- the percentage of herniated foetuses which adds credibility to your work and gives the reader information on how frequent this abnormality occurs. Your section for current does not have a lot of information, there is only one reference available for your recent findings. This section of your project needs to be further researched before the submission date.

There is more than one hand drawn image is which fantastic! The colours used for it are a bit too bright, however, this shouldn't be too difficult to change, perhaps just adjust the brightness of the picture on paint, or whichever program the picture opens up with on your computer (this is just a very minor critique. The fact that your group project has more than one student hand drawn image shows adherence to the requirement for the project guidelines.

It was great to see only one reference list, as opposed to different reference lists for each section in the project. Your reference list appears to be long, with 24 references however, 16 of these references part of the timeline. More research papers need to be included to make what is already an amazing project, better!

A video of the GIT and the rotations that occur during development would be rotations would be great visual representation of this system due to the nature of its development course. Perhaps you could find one off YouTube or create one.

Overall, this is a good project page, well done group and best of wishes!

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You have covered the key topics in relation to GIT. There is a good progression of topics, beginning with a GIT system overview and moving into more specific foregut, midgut and hindgut explanations. There are no subheadings under Hindgut however in the content box, the subheadings found in the hindgut section could be listed in the content box. In the explanation of the organs there is mentioning of the earlier embryonic weeks of GIT development. This may be important to set up the basis on which the fetal development begins. The page could add an introduction section to mention mention that your page focuses on fetal period of development, just for the knowledge of readers so that they know the page focuses on fetal development. The GIT system overview can be included under the introduction.

There was a good use of diagrams, in particular the hand drawn diagrams of midgut herniation and retraction of Midgut. This diagram shows a good understanding of gut formation and is really helpful in explaining it too peer level audiences. Also the diagram of large omphacele in the deformities also shows good understanding. However diagrams would really help wen explaining the Foregut organs like the oesophagus, stomach, liver etc. Reading the text is pretty heavy and pictures and videos would really help in supplementing the text. Images would also be really good for structures like Peyer’s Patches and Interstitial cells of Cajal.
The timeline shows a good overview knowledge of gut formation and is useful for readers to refer to keep in context when reading the more detailed descriptions further on in the page. The other topics substantially cover all the other topics to a level around teaching level. Further deeper research can be done in particular to do with ‘recent findings’. However group you guys has not included a ‘historic findings’ section which I know you guys will do before the deadline. You guys have discussed recent findings but haven’t discussed current research models. Also there could be more information on the recent findings. The ‘anorectal deformities’ and ‘cloacal extrophy’ descriptions could be added to the main deformities section and it could be emphasized that it is a hindgut deformity.

References and citations are done correctly. The link in the recent findings subsection could also should be added to the main reference subsection and removed from the recent findings subsection. The citation number hyperlinks are meant to be put at the end of paragraphs or sentences instead of at the front of them as was done at the start of the ‘Oesophagus’ subsection and in ‘Stomach’.
In foregut, midgut and hindgut subsections there were a lot of text but there wasn’t enough in text citations within the text. Instead of putting the citation number hyperlinks at the top under the headings they could be included in the text or at the end of the texts. There are little errors like in Hindgut section, under Cloaca partitioning, ‘esenchyme’ was written instead of ‘mesenchyme’.
Otherwise your page is really good and comprehensive. Too go beyond the normal teach level of information you guys could add more information to historic findings and recent findings. A good recent findings section will give a good contemporary twist to your page, too keep the readers interested.

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The overview is quite short and lacks citations and images, however this is understandable seeing as it is a draft copy, but please make sure the overview informations are cited and images are included. The information uploaded so far is structured based on the division of the gut into fore-gut, mid-gut and hind-gut, and very easy to follow.

An extensive timeline, however the presentation can be improved as this timeline takes a lot of space and consists of a single word or a sentence. Maybe adding more information in the timeline or condensing the timeline in a table format.

I don’t understand the recent findings section as only one research paper has been considered. If more will be added then that is fine however when writing about these findings it’s good to incorporate it with other findings rather than simply summarising the results of one article.

Foregut, midgut and hindgut are well covered including innervations and structures of those areas. A range of format is used such as table, dot point and full paragraphs, which neatly tie all the information together and allows for a break in between paragraphs. Student redrawn images are a great source and you have referenced from where you have obtained the original image. No images are used for the foregut even though you have mentioned a few organs in detail. Furthermore, it is best to keep your formatting consistent as the dot points in the foregut section differs to those in midgut.

Detailed examples of deformities are present in the gastrointestinal system, however more deformities should be looked at and included. Deformities are also mentioned under the subheading of hindgut (Anorectal deformities, cloacal extrophy, and developmental problems), which might be best moved to the deformities block of the project page. This redrawn image is clear and labelled, however there is no reference.

Overall the project page is interesting, easy to comprehend and follow, however certain layout issues should be addressed and more information added.

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This group has done exceptionally well at referencing their information and has a clear references section at the end of the page, (with the exception of the recent findings article which can be fixed up during the editing process). I particularly liked the structure and layout of the page and found it extremely organized and easy to navigate.

A point for improvement I’d like to suggest in the introduction is to focus on introducing the process of fetal GIT development rather than on the post-natal structure as that way you can set the scene of what the project is really about. It would be a good idea to summarise the purpose of the page and it’s contents. With the developmental timeline, it would be a great idea to put that into a table and expand a little more on each stage that has been listed, for example include the implications of development of Cajal cells in the small intestine.

Additionally, it would be a good idea to include images of the development process to help illustrate rotations and break up the text. I would also suggest to find and briefly elaborate another one or two articles for the recent findings section. There are some links to references under the foregut heading that don’t seem to be referring to any text and should be editing out or moved to the relevant position in the text. Another suggestion is to shift the developmental problems subheading from the hindgut section to under the deformities section as I feel that would be more relevant there.

The midgut and hindgut sections were written very well with relevant diagrams to support the information given. The use of original hand-drawn diagrams with colour helps to make the page more visually appealing and interesting to read. Overall the project was coherent and consistent over the different headings. I found it to be well structured and definitely informative. Good job!
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‘GIT system overview’ section is good but requires more information to introduce the GIT and what the page is going to have information on. Timeline could form part of this section and could also preferable be in the form of a student drawn image or even a table. The overview section also contains no in-text citations. It’s a great idea to split the GIT into the three parts: foregut, midgut and hindgut to aid in understanding. There is not much information on recent findings without any mention of current models as well so perhaps it would be best to address this before final submission.

In the foregut section there is not much mention of blood supply or innervation as was done for midgut and hindgut. Student drawn images are very impressive and referenced correctly with the student template, description, title and copyright information. The features of the midgut section could include some histological drawings or images. The ‘abnormalities’ section does not contain many in-text citations in one of the paragraphs and could include more deformities listed and described with more images, as well as information on how to treat and manage such disorders later in life. There is also no information or images addressing historical findings or current models so this needs to be looked into.

The references are correctly done and ordered, and are present at the bottom of the page. Some of the in-text citations aren’t throughout the text like they should be, for example, in the stomach, liver and gallbladder, and oesophagus sections.

Overall, good effort so far but more extensive research needs to be conducted for models and findings and more information for Abnormalities, as well as a few minor edits to make the page present more nicely.

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Good introduction, initial description of fore/mid/hindgut with listing of respective structures gives the reader an anatomical starting point. Fetal development is presented in appropriate depth. There is no acknowledgement of embryonic origin, research or abnormalities. These sections should feature in the introduction to present all parts of the report in the intro. The three separate timelines defeat the purpose of a timeline. These should either be merged into a single large timeline and remain at their present location or moved to introduce the foregut/midget/hindgut sections later on. Recent findings has a single study which is covered in good detail though 2-3 more studies would allow the reader to further understand current GIT Research.

In foregut section the dot-points used should match your subheadings. For example duodenum development is covered in the stomach section but is not mentioned in the subheading resulting in its development being hard to find without trawling through the text or “Ctrl-f”. Additionally you seemed to have missed out on pancreas development entirely. Foregut could also use some more images 2-3 would be suffice. Midgut development has great information, strong table, 8/8 drawings(captions required though). Inclusion of histological features gives viewer a microscopic perspective on development. Hindgut cloaca partitioning content is well worded though references are lacking.

Anorectal deformities sections should be moved under the Deformities section. The type of dot-point style used should be standardized. Too few abnormalities in the deformities section, though after the hindgut deformities are mover there should be sufficient. There are no references supporting the possible causes of Gastroschisis. The referencing it very good unlike other pages there are no random reference subheadings. In overview format wise quite attractive, information is adequately in-depth in all sections, introduction fails to address whole page, referencing is great for a draft (exceptions being “introduction” “Liver, Gallbladder and Bile Duct”), some captions aren't present, abnormalities in development section should be moved into deformities/abnormalities section.

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The introduction is good as it accurately describes what the GIT system is about and the anatomical positions of the features in this system. It also briefly highlights the development stages at embryonic and fetal stages, however ‘embryonic development’ should be mentioned in a little more detail to understand how far in development the fetal stage begins. I also think the introduction should include a sentence or two describing how abnormalities in such organs can lead to these diseases. Basically a bit from each major subheading should be incorporated including current research as an introduction is a summary of the whole page. As for the ‘timeline’, it would’ve been more appropriate to place the timelines under each section, e.g foregut timeline under the ‘foregut’ subheading. This is because viewers would be confused on why there is so much difference in development in one section of the page. A glossary list should be incorporated in a separate subheading to define some of these words such as hematopoiesis so that viewers can fully grasp the information.

The information under recent findings is quite interesting and relatable to the content which is GIT fetal development. However, I believe more findings could be incorporated under this subheading. The information under each organ of the three ‘guts’ are quite detailed in fetal development which is good and shouldn’t be too difficult for the viewers to understand. However, I believe the group could include information on the function of these organs as well. The structure of the information under ‘guts’ does not flow in the sense that the midgut includes features and structure whereas the other ‘guts’ do not. The innvervation and bloody supply of the hindgut should be incorporated in a paragraph instead of being listed like that. All the deformities should be places under one subheading to make it easier for viewers to navigate. The abnormalities were also concise and related to the topic. Overall, the content is relating to the topic of the project and addresses key points. It also shows good amount of research, however there seems to be too much information in some parts which could be reduced a bit. The project needs a coherent flow of the structure.

As for images, there needs to be an image under introduction which includes all features of the GIT tract. There are a lot of potential images missing under each subheading except for the ‘midgut’ section. This shows that there has been one person working on this section or one section being focused on in comparison the others. The information used to reference the images is missing in some images such as the ‘Human- fetal week 10 sagittal plane D.jpg’ (although this is uploaded from a different user so this is understandable. However images such a ‘GIT 2.jpg’ need more information including ‘student template’ as well as the reference where the image idea may have come from. Also, if this is a hand-drawn image then please state this as one member did in ‘Week 11 midgut herniation.png’. Overall, I enjoy the use of self-drawn images as it makes it easier to show what the content is saying without going through the stress of looking for an image online that doesn’t relate to the content. However more images definitely need to be added. The use of footnotes is also good and indicates what the images are showing.

There are sections where incite referencing are used, however some sections are void of them such as the ‘introduction’ and ‘Liver, Gallbladder and Bile Duct’ (the [6],[7] should be placed next to the text not above the text. The use of a ‘references’ subheading is good the same references have been combined into one number showing that the group knows how to make the references set out. The use of a table in formatting the ‘Percentage of Foetuses Herniated’ is great and shows more that the group has done research. Overall, this is a good project and if the group makes edits based on the peer-reviews received, this could enhance their project.

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A good introduction to the page but only outlines the developmental part of the project. Don’t forget to include other sections as well like current findings, abnormalities, etc. Also, no need for the hyphen for foregut, midgut, and hindgut. The development timeline is really good. Its very concise and well-referenced. It could be improved by tabulating the whole thing and maybe try to fuse the three sections together. Also, add an image or drawing of the development of the system. It will definitely help in terms of understanding what is happening at each stage. On recent findings, it’s not as good as the other groups but it’s definitely a start. Most groups write about 2-4 research articles for their current findings sections. As for the development section, each section is very detailed and informative. Maybe add a few images for the foregut section because images are really helpful. As for midgut, great to see images and student drawings. Good job on that. The same can be said for the hindgut section. It’s written well but maybe put the deformities in this section with the “Deformities” section. Deformities (abnormalities) section is good. It is detailed and the image used clearly shows what the disease is like. Maybe writing about 1-2 more abnormalities would make this section better.

It terms of citation and referencing, midgut section did the best job. I recommend the other sections to look for a lot more related material. I understand that this topic was divided depending on the region of the GIT, particularly the development section, but make sure to reorganise each section to make the page coherent. As for the images, most of them are well referenced. It wouldn’t hurt to add a few more. It’s great to see a lot of student drawings. Overall, a good project page very detailed in most areas but very little in referencing. In summary, focus on adding more references, making the whole page coherent, and a few more on the abnormalities.

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The introduction provides a good basic outline of the overview of the GIT. Although, there are no in-text citations in the introduction and all sub-headings are not included into the overview. Be wary of spelling errors such as “GIT (Gastrointestinal Track) consist of the Fore-gut, Mid-gut and Hind-gut” that should read Gastrointestinal Tract consists of the foregut, midgut and hindgut. This section would be better it was expanded upon and images were added. The timeline provides good detail, though would benefit by better formatting and organisation of the information, maybe putting it all into a table, by week will tidy it up.

Adding images for the sections will definitely be beneficial. The images hand-drawn are great, although the colours used make it hard to read. If you plan to add anymore drawings, try and use dark colours that allow for easy readability. The images already uploaded are missing copyright, referencing and “student template” information for images such as “fetal week 10 sagittal plane”. I would suggest you look up the tutorial for uploading images on the pages as Mark has extensive information for the proper steps required for uploading images.

The deformities section should be re-titled abnormalities as per the assessment criteria and would ensure the group is following similar structure from the other projects. Again, adding an image per disease would be great. Try and do about 1-2 more abnormalities. Great job on putting all the references at the bottom of the page, it makes it very neat and accessible. Overall, a good project just needs a few edits.

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A good overview of the GIT, very descriptive. This section would need some referencing as most of this info isn’t exactly common knowledge. Some of the sentences seem too short for me e.g. I would reconfigure the third sentence and combine the fourth and fifth sentences into one: ‘The GIT (gastrointestinal tract) consists of three regions: the foregut, midgut and the hindgut. The majority of the organs are located in the foregut, including…..’. You also need to make sure not to use capital letters in the middle of sentences.

The timeline is sort of well organized; it’s good that you have it separated for each region so they’re not all muddled up together, but is the info in dot points under the week, or is it just written next to the week? It needs to be kept consistent. I feel like this section is a bit too spread out as well, a large portion of the left hand side has text, while the entire right side of the screen is empty. You could possible put in a picture showing these 3 regions of the gut to fill in the space? Or maybe format the info into a table, it would make it look more formal and structured. The proper referencing technique should also be used here, not added hyperlinks.

The recent findings area is a little sparse, so you should try to find a few more. The title does say findings (plural), so maybe add at least one more. The foregut section is very extensive on the information provided which is good, a lot of research has been made. Visually however, it looks a little bad as all that can be seen is a mass of text. This can be alleviated if the same thing is done as has been with the midgut and hindgut region: the use of bullet points, a small table and the use of images to offset the slabs of text. It makes it more visually appealing. Unlike the midgut portion of the page, if the images are hand drawn, make sure they are clear, legible, and with colours used that will not strain the eye. For the images drawn in that section are messy and the labels hard to read both due to the colour of the pen used and the handwriting. In both the foregut and hindgut, referencing needs to be done. There are slabs of text in both sections where no references are made.

The deformities section is good, kept simple with no extensive explanations. Are there only 2 possible deformaties? If so, might be good to write a sentence mentioning that. If not, would be good to have at least 2 more deformities listed. The image drawn in this section is very neat, I like it a lot. The only problem with it is that it’s too small, making it hard to read some of the labels.

Overall, I think this page is very well done in terms of content. You have a lot of text, but I think it could do with some more pictures especially to offset some of the large slabs of texts in some areas. Make sure the pictures you have a clear and neat, and make sure you are referencing and doing it correctly.

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Overall this is a good project; I enjoyed the tailored diagrams and presentation of information in a succinct manner. Information is presented in a logical and coherent manner. The presentation of information into specific components such as foregut, mid gut, hind- gut is great.

The quality of research is exceptional and well presented. Specifically, the subsection of mid gut and the use of visual aids assist immensely in the translation of complex concepts into simple ones. The use of dot-points succeeds in summarizing the information into easily digestible sections. This also improves the clarity of the page. The use of subheadings also assists with the logical analysis of the project.

However, the referencing could potentially be more extensive. A further expansion on current research model and findings will prove to be instrumental in generation of a solid understanding of the project hand. I would recommend splitting recent findings into current research models and historic findings.

It would have been beneficial to see more information on the foregut section, as this would have provided a pronounced understanding of the topic at hand. It would assist in the comprehension of the data if the timeline were tabulated. Further expansion of the abnormalities would be needed. It would be great if the abnormalities in the hindgut were moved into the abnormal section. The grammar and punctuation is sound and the readability is good. The presentation of information is lucid and shows a sound understanding of the concepts involved.

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The introduction part of this project provided a good overview of the gastrointestinal tract and its components, also mentioning briefly the changes that occur in the fetal period. However, care must be taken to not capitalise words that are not needed e.g. Foregut, Midgut, Appendix etc. Although the information in the ‘timeline’ section is relevant, its formatting needs a bit of review as there are inconsistencies between the foregut, midgut and hindgut parts. It also seems that the in-text citations have just been arbitrarily placed in chronological order, with each line having a new reference. Also, this information may be better presented in table format to improve readability. Some simple editing may be needed to fix this.

The section on ‘Recent findings’ has some good information, however the reference needs to be properly cited and maybe a couple more articles would help give this part some substance. I thought it was effective to have the GIT split into the foregut, midgut and hindgut and then detail the fetal development under those titles. This gave the page a good structure. However, adding some images, both from online and student-drawn to the foregut and hindgut sections would help improve the aesthetics of the page. The hand-drawn images on the midgut section are effective learning tools to a student, but maybe could be drawn a little neater with darker colours as the blue labelling is difficult to read. They should also be captioned. The use of a table to show midgut herniation of fetuses was a good tool as it makes the information easier to read also.

Lastly, the section on abnormalities was well-detailed and I liked that the deformities were split into a definition and cause. An image of gastrochisis may be helpful for a reader to visualise the condition though. The in-text citations in this part were properly done and a long list of references being at the end of the page made the project look neat overall. Areas of improvement may be some simple formatting changes and evening out the information across sections, however a solid project so far.

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Gastrointestinal

In the overview section, the words “GIT” suddenly are used without any explanation as to what abbreviation it is for. Change to “The gastrointestinal (GIT) system is a ….”. There are also some punctuation errors with capital letters being used mid sentence, and words like “till” being used instead of “until”. Adding a picture to the introductory section would make it visually appealing to the readers.
In the fore-gut section, there are not any pictures and make it really long and dreadful to read by first look. The explanation of the oesophagus being occluded and recanalized is a bit hard to understand and could use some further explanation / rewording / diagrams to aid. I noticed in the GIT lecture that the rotations that occur in the mid-gut was a hard concept for me to understand, you should definitely add a gif / picture to portray this nicely to the readers.

Overall, I think the tone of the page is very dry, and doesn’t include as much information as it should. You should include more detail, and especially some background information as to how and what the structures arise from, as well as explaining the overall function it will hold in the adult.

The reference list seems really small, or most the text doesn’t seem relevantly referenced in general. You should check over the reference listings before submission. For the timeline I think it’d be better if you put the fore-gut, mid-gut, and hind-gut were put together, so that we can see the overall development, rather than the individual development of the GIT system.

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This project overall is very good with a lot relevant information. There is some use of images and hand-drawn images that are excellent. It would be good to see more images, perhaps to complement the timeline section. It is clear the group have worked well together to create a wiki page that flows well and covers all the organs of the gastrointestinal system. All the citations formatted correctly and it is good that all the references appear in one long list at the end of the page. There is still room to add tables, maybe to summarise the timeline. Other groups who presented their timelines in a table achieved an element of wiki-sophistication. There are a few spelling errors in some of the sections (specified below) which need to be corrected so as to not interrupt the flow of information when the reader is reading it. Again, there are only minimal errors or problems with this page, overall it is excellent!

The section on the midgut is well presented and thoroughly researched, well done! It is easy to follow and the way it is described makes it easy to imagine visually. However just double check for typos, for example “to that of” is spelt “tot hat of”. Simple error that is easily fixed. These hand drawn images are excellent. The colour coding and minimal use of words is very effective in supporting the written material.

The hindgut section is also well written and there is a lot of extensive information. Also double check for spelling, mesenchyme is spelt “esenchyme” in one of the sentences. This area of the project is lacking images detracting from its readability and level of interest.

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This project page has thus far been completed with really great effort. The introduction is a good detailed description of the gastrointestinal system consisting of all the corresponding organs. Good to see a timeline of all the events, might be useful to format this into a table since it is so extensive. The ‘recent finding’ section is done well, will however need more info maybe including other studies. Try to look through the GIT development lecture content, there may be some more studies mentioned and these could also refer to others. The ‘foregut’ section is really well detailed and easy to understand, although it would be nice to see some images, drawings or even tables as done in the ‘midgut’ section. The ‘midgut’ section is great, in its formatting, info, visuals and citations, and the drawings in particular are a really good effort. It would be great if you could try to re-upload the drawings, as it is hard to see some of the labeled structures clearly. In the section describing the ‘hindgut’ there is a good use of in text citations, just be careful as some parts don’t have them so they may need to be added. Also there are some minor formatting adjustments that may need to be made with some of the dot points. Lastly the ‘deformities’ section is done well, easily understandable and a good structural layout. Might want to add a few more, maybe the ‘Anorectal deformities’ sub heading could be moved into the big ‘deformities’ heading.

Finally this page is done well considering there are a number of sections that have to be covered. Some suggestions that could be helpful include; adding an additional heading for historic findings which is listed in our assessment criteria. To help find info for this try to search under the “Explore” tab on the left had side of the embryo page, clicking on the sub heading ‘historic embryo’. Also a useful source is the unsw library as it spans a longer period of time and following the unsw search then research the article in the pubmed site. For the in text citations try to add them after the content rather than before as it’s not clear which parts are from certain references that have been found. Adding some more images especially in the ‘deformities’ section would be good to see. There are only a few minor changes that may need to be addressed. Otherwise you just need to do a little more research to complete the page. So far good work everyone, keep it up. Good luck :).

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I believe more of what the page hopes to achieve could be added to the introduction. These outcomes could add to the overall understanding and experience of the page. Also, remember to at least acknowledge the historical findings, recent findings and abnormalities section in the introduction (just state how this page will attempt to cover those areas- just a suggestion though!)

The development section has an excellent choice of headings and subheadings. There is correct referencing and strong evident of significant scientific research. I do believe however that this section could be summarised with more information presented in a table. There is also an excellent addition of images and hand-drawn diagrams, which adds to the overall understanding of the section. The hand-drawn images clearly display an element of teaching at the peer level and a strong overall understanding.

More recent studies could be added to the ‘recent findings’ section. Only one is currently presented at the moment. It is well explained, correctly referenced and informative though.

I can not find a ‘historical findings’ section?

I believe more abnormalities and deformities could be also added. This section is very informative and correctly referenced. I particularly enjoyed the addition of the hand-drawn diagrams- it was clearly labelled and aided in the overall understanding. Excellent work nevertheless.

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In this review I intend to highlight the positive features of your project while pointing out some areas that need improvement, in light of the marking criteria provided.

I really like the overview on of the topic, it is clear and succinct. However you could elaborate on some of the areas if time permits. I think a developmental time line you have presented is a great way to summaries all the information. I would also like to mention that this summary is very well referenced and gives an over view of the significant event is GIT development. However I think that this information would be best presented in a tabulated form. Perhaps you could use the following layout: Column1: Week, Column 2: Foregut, Column 3: Mid-gut, Column 4: Hind-gut. It would also be a good idea to include images or diagrams. I particularly like the hand drawn diagrams, they really compliment the text and help visualise the different stages of development.

However are two issues with this project, there is little information on current research. I suggest looking up emerging technologies, drugs, treatments for congenital abnormalities in relation to GIT development. You also need to address the topic of Historic Findings, I suggest using textbooks from the library, the UNSW library database and UNSW embryology page to discover how our understanding of GIT development began and how it has changed.

A great start to the project. Make sure you organise and structure the page under the appropriate headings before you submit the project. Good luck!!

----
Introduction is good as it describes and gives an overview about what is happening in the fetal period for foregut, midgut and hindgut. However, it would be better if it mentions that the project is focusing on fetal development, abnormalities, current researches, etc.

It is clear to separate the timeline of GIT development for hindgut, midgut and foregut. It is well-researched with much information in this section. However, it would be easier to follow if a table is used and images are included.

The hand-drawn images can explain the development well, however the blue colour for labelling is a bit difficult for reading. It would be better if a darker colour is used.

It is a good idea to explain the abnormalities in definition and the causes. Some more abnormalities can be included as well as images for better understanding.

There is only one reference in recent findings. More researches could be done in this section. Also, a section about historic findings could be included as well.

There are a few spelling errors, such as “esenchyme” in the hindgut section and “tot hat of” under midgut section. Some proof-readings are needed.

The referencing is overall good, but some more researches have to be done under some sections (abnormalities and recent findings). It is easy to follow as there is a reference list at the bottom of page.

It is overall a good project as the development during fetal period is well described. However, more information about recent findings and abnormalities could be included, with the use of images to illustrate the contents.

----

The introduction to the gastrointestinal system development is ok but needs work on as to indicate what will be covered below and any other noteworthy information. However, the introduction does briefly describe the parts of the GIT system as they reader may not be aware of all the structures. Overall, sentence structures need to be improved on as they may lead to confusion. In addition to this certain areas of development have been missed out and need to be included. The strengths and weaknesses are covered below;

====Strengths====

• The timeline of GIT development in the embryonic period has been well written and is very concise in conveying what happen in each week.

• Originality is quite important as some images have been drawn up and uploaded. These have been done well and indicate that group project contributors are showing dedication.

• Most Images have an image name and an image description.

• Referencing with in-text citations and no random references in between paragraphs.

====Weaknesses====

• Abnormalities section of the GIT system is quite lacking and so more information on defects as well as image should be provided.

• Certain organ development areas are also lacking ad need to be included with those already mentioned.

• More in-text citing should be used and not only centered in some areas.

• A tabulated form of the timeline would be useful as to allow it to be clearer.

• Some footnotes are placed in the wrong areas and should be within paragraphs and not be separated.

• Headings need to be consistent such as using the same font and size.

----

Introduction is good with brief background information on the anatomy of the GIT which is an appropriate starting point for the readers. Fetal development is also described in the introduction, however I suggest including more information on embryonic period and how that leads to fetal development so that the rest of the page can focus more on the fetal stages. I also suggest including parts of each of the major subheadings in the introduction such as the common abnormalities and the recent finding. An image illustrating different organs of GIT can also help with better understanding of the anatomy. There is no referencing in the introduction to support the information provided.
Regarding the timeline section, the information needs to be tabulated in order to make it easier to compare between organs. Another alternative is to include a small timeline for each of the organs at the beginning of each section. It is very good that each stage of the timeline has been separately referenced; this shows the extensive research that has been conducted.

The recent finding section focuses on only one study in 2006 on hedge-hog signalling pathway. There are a lot of interesting and more recent studies that can be included in this section. As a starting point, you can search for recent models that help in better understanding of GIT development.
The information under each of the foregut, midgut and hindgut is very detailed and comprehensive; however the structure does not flow through the whole page with mid-gut including different subheadings and diagrams. In my opinion you should break up the foregut and hindgut sections into smaller subheadings and use diagrams like the ones used for midgut. Potential images can also be used in these sections. Additionally, the anorectal deformities under the ‘hindgut’ section can be placed under the deformities section. The “Midgut” section includes very good information and the drawings are helpful in understanding the concept however they need to be captioned.

This project does not include historic findings. I understand that this section is a bit more difficult as it is hard to find information on it. A suggestion I can make is to search for old articles in PubMed (by adjusting the year) which can include key historical events. Review articles that summarise historic findings related to GIT development may also be helpful. The abnormalities are precisely discussed and are relevant to the topic but as mentioned before, I suggest putting all the abnormalities under one subheading to make it easier for the viewers to navigate.

Overall, the main key points are addressed in this project and the content demonstrates extensive research and a good understanding of the concept. In order to facilitate learning and to make it more interesting and understandable for viewers, some of the text can be summarised in diagrams. Dot -points can also be used in some parts instead of paragraphs. The use of hand written drawings was creative and aided in understanding however I would suggest stating that the drawing is handwritten in your page. If the drawing is copied from another image, then the source of that image needs to be included as well. Also a more complete description of the image will make it easier to understand.

----
I think that the ‘Deformities’ section should be renamed to ‘Abnormalities’ and I am not sure if that is because it is the correct term but every lecture and similar page on the Embryology wiki uses the term ‘abnormality’ to describe abnormal developments. The page also needs to be more referenced more in some areas (e.g. the possible causes of Gastroschisis section) so as to allow your audience to read more into the text you have presented and give some citations to your information. Some sections are also suffering from a lack of information (e.g. ‘Recent Findings’ – more articles and ‘Abnormalities’ – more abnormalities) and I think some more research would definitely rectify these weak points.

I really liked the use of your own drawings in some of the sections and I think this demonstrates that you understand the concepts. My only criticism is that the images are a bit difficult to interpret because the colours are really hard to see against a white background. It would be good if you included some images from scientific literature as well to give more links to scientific papers.

Overall the page needs some more work and I think some more research and referencing will definitely go a long way in making this page better. You have the basic scaffold for you page and you only really need to develop some more detail in these areas.
----
A good introduction to the Gastrointestinal system giving a broad overview of the system. The timeline is effective in giving a general perception of the gastrointestinal system development. However maybe this could be put into a table format or add pictures to refer to specific or significant development.

There is a great deal of information that is presented in a strong manner however there is a scarce amount of images. Images can help summaries what some of the paragraphs communicate, tables would also be beneficial to make the page more inviting. Otherwise the page appears to overwhelming with just written content and no visual content to reinforce concepts and information.
I’d like to acknowledge the hand drawn diagram and the efforts taken to do that. Great job.
There is an inconsistency in the amount of information throughout the page. Some sections lack information more than others, however this can be a room for improvement to insure further research is done in sections like “recent findings”.
In regards to referencing, I found that it was not as bad, however more referencing in some areas would benefit.
My biggest criticism is that the page wasn’t coherent and could flow a lot better with communication with each other and figure out a systematic pattern in each section of the GIT that it is broken down into.

Overall, you should look for a balance between information and pictures that complement the information you are trying to get across. Aim for a photo each section. Also focus on the coherence of your page as this will make it seem professional and makes understanding everything easier a the page flows.

----
Timeline is very clear and easily shows the order of developmental events that occur. Good detailed information about the development of the foregut, midgut and hindgut however more diagrams could be used in the foregut section. Good description of the deformities that can occur and the possible causes however there is no reference for the possible causes of gastroschisis. The recent findings could do with a little more detail or possibly reference another recent finding.

|}

==Discussion==

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 20:38, 13 August 2014 (EST)

Alright so lets choose a topic quickly before it gets taken. I would like all of you to post 3 topics that you would like to do (here) in order of importance and the topic that gets chosen the most will win. This is the only way I could think of in order to decide, so sorry. By the way Cardiovascular is taken so we cannot do that any more. My three choices are: Gastrointestinal System, Immune System and Placenta. What are yours?

i choose renal, head and neck, GIT --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 22:22, 14 August 2014 (EST)

Im thinking GIT. Everyone so far has said GIT so I reckon that might be the best option as i think it will be relatively easy to understand and follow with the whole mid gut, hind gut formation ect.
--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:58, 15 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 10:16, 16 August 2014 (EST) I have just reformatted your project page heading as the major heading (single =) and capitalised the words). All page sub-heading (two ==).

z3415141: I am going to be looking up research of the midgut.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:08, 20 August 2014 (EST)

I choose to research on abnormalities of the GIT system--[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 13:14, 20 August 2014 (EST)

z3375627: I'm going to be doing Hind gut development research --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:10, 20 August 2014 (EST)

z3414515: I will be researching foregut. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:12, 20 August 2014 (EST)

Alright people lets get some work done on this project. I hope everyone could at least write up few paragraphs on their chosen section by Tuesday. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 22:18, 30 August 2014 (EST)

--[[User:Z8600021|Mark Hill]] ([[User talk:Z8600021|talk]]) 22:47, 30 August 2014 (EST) I agree, times a wasting. While you have met the required addition of references, tarts all that is currently on your project page.

--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)The reference below might help you guys.
<pubmed>12943221</pubmed>
--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Is it only me or is everyone finding it hard to differentiate between embryo and fetal development?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:23, 2 September 2014 (EST)

Yeh I agree there are so many times where they talk about it as one in the same thing. Just have to read really carefully as we don't want to cross over. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:46, 2 September 2014 (EST)

Also with what you have written so far about the oesophagus, it looks good but what are you doing about referencing. Are you just keeping a list that you will put down later or are you getting the information from the resources that you found last week?? --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 14:53, 2 September 2014 (EST)

I have my references saved on my laptop so when the time comes I can relate the information to specific reference. How are you coming along with your research so far?--[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 00:08, 3 September 2014 (EST)

Just been reading heaps to make sure I get the information right. I'm trying to get a really good understanding of the midgut rotation as I believe it is a critical part in the development of the ftus. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:31, 3 September 2014 (EST)

I am still waiting for some information from z3375627 and z3415242. Common people get moving!!! Also I meant that in the nicest way possible :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:52, 3 September 2014 (EST)

I have found a picture to go with the adnormality that i am doing however i will not upload it until everyone is ok with it. I will work to add on the first abnormality i have started and done and continue to research on a second one. If i come across any useful articles for you guys i will post it on this. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 19:02, 9 September 2014 (EST)

Show the group in class your image so we can discuss on it. Also I know everyone must be busy with mid semester exams or assessments so I appreciate the effort you guys are putting in so far. BUT do remember as soon as the mid semester exams are over we need to pick up the pace or pull up our socks for this embryology project. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:27, 10 September 2014 (EST)

Common people lets get a move on. I have put up some information on my section though it is on the embryo period, the fetal period is in progress and in detail. The embryo period is only there as a guideline to understand how the stomach actually attains its shape. --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 12:47, 16 September 2014 (EST)

i have come across some research articles on omphalocele (abnormality occurs in week 10-12 YAY ) just reading through them as they are pretty long and abit difficult understanding so i'm trying to put some stuff into a paragraph or two will try and upload the stuff for it by this week sometime. cheers --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 21:50, 16 September 2014 (EST)

Alright this is the week to really get a good chunk of it done now that most of our mid sems are over. Not sure if anyone else has any good youtube videos, but because we only get one I'm gonna put this one out there relating to midgut rotation: https://www.youtube.com/watch?v=AscKR_cQExY --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:09, 17 September 2014 (EST)

Also we need to start our list of references so I reckon we just put them down under this heading. Leave the references at the bottom of the page ie. write above the heading references.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 08:18, 17 September 2014 (EST)

i found a simple sketch drawing of omphalocele just so we have some picture on our page but i don't want to put it on the page yet incase you guys don't like i and since we cant delete it once its up so after your approval i will put it up also i am trying to find good video on organ development since im sure alot are formed by week 10 as i have read in articlese. --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 00:42, 24 September 2014 (EST)

Apologies with my lack of input on this. I’ve added a bit of the Cloacal partitioning and deformities that I’ll expand upon. I’ve also found some great pictures on some of the other GIT deformities. If I’m unable to source permission for them, I’m happy to recreate them --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 07:55, 24 September 2014 (EST)

Definitely put that picture up about Omphalocele. That will work well because I'm talking about midgut herniation so if I talk about it in my stuff then I can just link it so that when you click on it goes down to the bottom of the page to where you talk about it in abnormalities. Not exactly sure how we do that but I'm sure we will work it out.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 13:02, 6 October 2014 (EST)

Hey all just wanted to note that when your referencing from now look at the editing page to see what mark does so that the references are footnotes down the bottom of the page. Obviously you will need to change the reference in the brackets but you get the point. This means that when you do this all the references will come up down the bottom of the page. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 23:34, 6 October 2014 (EST)

Not sure if we are supposed to get rid of the references that we used for our group assignment but I just did because they were taking up uneccesary space on our page. Just thought i would say this here just in case we were not meant to.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 09:17, 8 October 2014 (EST)

Everyone please take off your student signature from the group page as it looks unprofessional. Thanks guys and girls :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 10:07, 8 October 2014 (EST)

We need to find recent research articles on stem cell on this weekend people. By this friday night please try to finish your section of this project so on the weekends we can focus on current models/findings and historical findings. Thanks group :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 13:00, 15 October 2014 (EST)

I didn't like having to get through all the peer reviews to get to discussion. I collapsed it for ease of use --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 11:51, 19 October 2014 (EST)

well done z3375627 for collapsing the discussion section. It makes a whole lot easier for us now :) and ALSO thank you z3415242 for doing the timeline table. It looks good but obviously we need to try to add a bit more information on it. Lets get our sections finished first people THEN we can worry about the editing. ALSO do not forgot to contribute a stem cell research paper on the facebook group so we can discuss it. Thanks :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 16:44, 19 October 2014 (EST)

ok so looking through the peer reviews the main things that people were talking about were: make sure that we tabulate our information, add more models and research findings and then there were things more related to the individual assessments. So its good that someone has started to tabulate our timetable but its a bit all over the place at the moment so we probably need to fix it up a bit. and then we really need to get onto the research findings ect.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 19:08, 19 October 2014 (EST)

People do not forget to add reference for the image within the image if that makes sense. And we need to finish our part of the project as well as current findings, models and historic finding by tomorrow night or by wednesday lab PLEASEEEEE. This is because we need to spend a day on editing the page overall as a whole with consideration to the peer reviews. ALSO we MUST have a gathering so we can do this editing together either on wednesday after lab OR thursday. THANK YOUUU :) --[[User:Z3414515|Z3414515]] ([[User talk:Z3414515|talk]]) 09:18, 20 October 2014 (EST)

Wednesday would be suitable for me if that is fine with the group also i have added a link of a recent finding under that heading can someone please check its ok to use so then i can start to summarise it, and for the stem cell presentation i have found this http://circ.ahajournals.org/content/125/7/883.long i hope you guys are fine with it. Also does anyone know any good link where i can get xray image or real life image of infant with one of the disease,it's hard finding image which allows permission for use if any of you guys have suggestion would much appreciate it thanks --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 10:17, 20 October 2014 (EST)

I cant find a place for x ray images sorry. Just had a look at that article you have under the current research on our page. I think it would be fine to use. I assume you were going to put this under the models section right???--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:00, 20 October 2014 (EST)

yes i was thinking that but I'm not sure if it relates with fetal development, i also found this http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009111
i think can be used for findings so i might sumamrise this first i think its more relevant then my previous link --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 10:45, 21 October 2014 (EST)

so i changed the table a bit to simplify it. I will explain tomorrow in class why when you click on some of the links it doesn't work. I worry a bit about the foregut section in the timetable because i feel as though its a bit embryonic heavy. But i think mark will be fine with it anyway. I think you might have said something ealrier about you talking to mark about it so we should be alright. so we just need to finish off the findings part and then make the last few changes and then we should be right.--[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 12:54, 22 October 2014 (EST)

I noticed that Midgut doesn't have appearance of villi. After gut return, week 9 has differentiation of epithelium in intestines. Week 11 villi appear in SI, with lining complete by week 16. If you don't have the time to add anything, i'll revisit again tomorrow night/Friday morning and add it in --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 23:41, 22 October 2014 (EST)

Ok just did it then. Tell me what you think. I also updated it to the timeline. I think our project is coming along well overall. Hopefully mark realises that we are trying to keep things as simple and as interesting as possible and we are not trying to kill the page with too much information. --[[User:Z3415141|Z3415141]] ([[User talk:Z3415141|talk]]) 18:49, 23 October 2014 (EST)

I guys i was just trying to fix some stuff and i was wondering where my abnormality table information went from the coding as without it i can't add information into the table, if anyone edited it could you let me know where the content is so i can fix up the blank boxes thankyou --[[User:Z3415242|Z3415242]] ([[User talk:Z3415242|talk]]) 20:59, 23 October 2014 (EST)

==References==

Won Kyu Kim, Hyun Kim, Dae Ho Ahn, Myoung Hee Kim, Hyoung Woo Park Timetable for intestinal rotation in staged human embryos and fetuses. Birth Defects Res. Part A Clin. Mol. Teratol.: 2003, 67(11);941-5 PMID:14745932. I used this in describing midgut rotation.
<gallery>

</gallery>

2014 Group Project 3

2014-10-23T09:20:44Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production. The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|300px|A)Foetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface. B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells (as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine contains mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis.
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

<pubmed>4075420<pubmed/>

<pubmed>23553304<pubmed/>

<pubmed>2960962<pubmed/>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>

File:Thymosin B4 detection in foetal developing ileum.jpg

2014-10-23T09:18:54Z

Z3415242:

A)Foetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular deposits located in the mucous of the gastric surface.

B)Stomach of adult with intense reactivity for Tβ4 (arrow)

<ref name="PMID20161756 "><pubmed>20161756</pubmed></ref>.
<references/>

Copyright
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2014 Group Project 3

2014-10-23T08:38:51Z

Z3415242: /* Current Research */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT (gastrointestinal tract) system is a complicated system that extends from the mouth of the foregut to the anal canal of the hindgut. Its function is to ultimately turn food that is eaten into energy. The GIT system consist of the foregut, midgut and hindgut. Majority of the organs are located in the foregut. This includes the stomach, duodenum, Liver, pancreas and the spleen. Overall in fetal stage of the foregut development there is more rapid growth of already formed organs and important structures such as muscle layers emerge as well as bile production. The midgut begins below the hepato-pancreatic ampulla and consist of the lower Duodenum, Jejunum, Ileum, Cecum, Appendix and the Ascending colon as well as the first two third of the transverse colon.In fetal development after the rotation and fixation of the midgut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. At week 11 midgut retracts back into the abdominal cavity and continues to grow. Hindgut begins from the left third of the transverse colon and ends to the cloaca (rectum). It consists of the left third of transverse colon, descending colon, sigmoid colon, rectum and anal canal. There is no rotation occurring in the hindgut instead it gets pushed to the left side by midgut during development.The colon matures and lengthens and the anal canal is formed.The following page will explain the key fetal stage development of each segment of the Gastrointestinal tact (foregut, midgut and hindgut), some current research and models used to explain GIT system fetal development as well as the common fetal stage abnormalities and briefly list common abnormalities occurring in the embryonic stage.

==Timeline ==

{| class="wikitable"
|-

!!!!! GASTROINTESTINAL TRACT DEVELOPMENT !!!!
|-
! Weeks !! FOREGUT !! MIDGUT !! HINDGUT !!
|-
| Embryonic Period|| '''Week 4:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Ventral outgrowth (hepatic diverticulum) of liver, gallbladder and bile duct ]

'''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver obtains a bright reddish appearance due to hematopoiesis]

'''Week 7:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach 90 degrees clockwise rotation of the stomach]

'''Week 8:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus Occluded lumen and vacuoles appear in the oesophagus]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Oesophagus The outer and inner muscle layers of the oesophagus development]
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Stomach Due to the stomach rotation, the duodenum is pulled into a "C" shaped position]
|| '''Week 6:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Rotations_.28Embryonic.29 Embryonic Rotations]
||'''Week6:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Cecum diverticulum appears]

|-
|Fetal Period|| '''Week 9-10:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Liver is 10% of the total fetus weight]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 12:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile formation via hepatic cells begin]

'''Week 13:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Liver.2C_Gallbladder_and_Bile_Duct Bile entering via bile duct into the duodenum gives the intestinal contents a dark green colour (meconium)]

|| '''Week 9:'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the small intestine]

'''Week 10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Midgut_Herniation Midgut Herniation]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Interstitial cells of Cajal present in the large intestine]

'''Week 11:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Retraction_of_Midgut Retraction of Midgut]

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Villi formation in Small Intestine]

'''Week 16'''
*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Appearance of Villi throughout the Intestine]

'''Week 19:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Features_of_Midgut Peyers patches formed in small intestine]

|| '''Week 9-10:'''

*[https://embryology.med.unsw.edu.au/embryology/index.php/2014_Group_Project_3#Cloaca_partitioning Proliferation of mesenchyme]

|}

==Current Research, Models and Historic Findings==

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0012160613005605
(I have found this can someone confirm its ok to use so then ill start summarising it thanks )
{|
|-bgcolor="FF EF D5"
|
===Current Models===

'''Fetal Intestine Transplant Injury Models'''

Using colonic injury models from both fetal humans and mouse it was found that the proliferative immature progenitor cells within the intestines could be expanded in vitro as Fetal Enterospheres (FEnS). Following transplantation after a in a colonic injury model, it was found that FEnS contribute to the regeneration of colonic epithelium by the formation of drypt-like epithelial structures that expressed region-specific differentiation markers. An overview of the process is shown in the digram on the right. This study revealed the existence of transitory populations of progenitor cells during the intestinal growth phase of both human and murine tissues<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

A group of cells with similar characteristics can be obtained from pluripotent stem cells. In comparison to progenitors in the adult state epithelium this population is characterised by distinct proliferative and differentiation potential in reduced in vitro growth factor requirements. Fetal enteric progenitors were found to transition into an adult state after induction in vitro via stimulation with high levels of Wnt. It was found that the same transition could be made using the injury models via in vivo transplantation. These cells give an insight into tissue maturation and provide an attractive source of transplantable progenitors for regenerative therapies<ref name="PMID24139758"><pubmed>24139758</pubmed></ref>.

[[File:Fetal Colonic Inury Model Diagram.png|right|500px]]

Diagram of Fetal Injury Colonic Transplantation Model<ref name="PMID3858813"><pubmed>3858813</pubmed></ref>

|}

{|
|-bgcolor="E0 FF FF"
|

===Current Research===

http://www.ncbi.nlm.nih.gov/pubmed/16369776

Recent Findings on Omphalocele:

In a recent research experiment, the Hh hedge-hog signalling pathway was believed to be a possible causative factor of omphalocele formation. The TM -inducible gene recombination system was used to show association of Hh signalling with omphalocele. Omphalocele was prominently observed in embryos from dams treated with the higher dose of TM (2 mg/40 g bw) but not with the lower dose (1 mg/40 g bw).<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>. The study observed ectopic Hh signal activity in the ventral wall region through del5-LacZ staining and a gain of function mutants of Hh signalling expressed defects in the body wall, therefore results suggested ectopically induced Hh signalling was a potential causative agent in a dose dependant formation of omphacele<ref name="PMID16369776"><pubmed>16369776</pubmed></ref>.

'''Thymosin Beta 4 Immunoreactivity in GIT system during fetal stage development'''
[[File:Thymosin B4 detection in foetal developing ileum.jpg|right|300px|A)Foetal stomach with Tβ4-immunoreactive granules shown by arrow. Arrow head show the Tβ4 granular DEPOSITS located in the mucous of the gastric surface.B)Stomach of adult with intense reactivity for Tβ4 (arrow).]]

Recent study collected data which suggested expression of Tβ4 (Thymosin Beta 4) peptide in human gastrointestinal tract during development. The study obtained 2 human fetuses, a male at 20 weeks of gestation and female at 21 weeks. Samples from the different segments of the, gut such as liver, pancreas, stomach, ileum and colon was collected.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

All the different intestinal segments including glands showed immunoreactivity for Tβ4 however each segments/sites had different levels of this. Highest reactivity for Tβ4 was seen in adult liver and pancreas while the lowest seen in the fetal developing liver. Interestingly granular reactivity for Tβ4 was seen in the epithelium that covered the ileal villi and even more in the cytoplasm of mucous cells ( as can be seen on the right). Peptide reactivity was also observed in the mucous of the intestinal lumen at 21 week of gestation.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>. The high level of Tβ4 its expression during gut development indicates its relevant role for development of the gut.

As a whole, the data indicated a differentiation stage-specific regulation and expression pattern of Tβ4 in the gastrointestinal tract of human as well as annexed glands during fetal development. It was therefore suggested that Tβ4 could play variety of roles in development of organs in the GIT system during organogenesis.<ref name="PMID20161756 "><pubmed>20161756 </pubmed></ref>.

|}

===Historic Findings===

==Foregut==

<html5media width="420" height="315">https://www.youtube.com/watch?v=uPBEgBIvRcI</html5media>

The foregut consists of the following organs <ref name="PMID19575677"><pubmed>19575677</pubmed></ref> :
* Oesophagus
* Stomach
* Liver
* Gallbladder and Bile Duct
* Duodenum
* Pancreas

Nerve supply: ''Refer to specific structures of foregut''

Blood supply: Celiac artery

===Oesophagus===

The primordium of the oesophagus is a portion between the respiratory diverticulum and stomach dilation. The oesophagus is a short tube initially but elongates significantly over time as the fetus grows. Oesophagus has an endoderm derived epithelial lining which proliferates. The epithelial lining also undergoes a series of transformations. Occluded lumen appears by week eight as well as vacuoles. With time the lumen is recanalized and the vacuoles combine. The epithelium of the oesophagus becomes stratified squamous during the fourth month. The development of muscle layers consisting of outer and inner layers, are recognised by eight weeks. The oesophagus contains smooth (splanchnic mesoderm derivative) and skeletal muscle fibres.<ref name="PMID22750256"><pubmed>22750256</pubmed></ref>

===Stomach===

Dorsal and ventral mesenteries anchor the developing stomach to the body walls. In the 7th week, the stomach undergoes a 90 degrees clockwise rotation about a longitudinal axis. The rotation is such that the right side moves dorsally and left side moves ventrally. The vagus nerve follows this stomach rotation such that the anterior surface becomes left vagus nerve and the right vagus nerve becomes the posterior surface. Since the left vagus nerve is located on the anterior surface and right vagus nerve on the posterior surface, they are renamed as anterior vagal trunk and posterior vagal trunk respectively. The growth of the dorsal wall of the stomach is faster than the ventral wall. <ref name="PMID9664826"><pubmed>9664826</pubmed></ref> The greater and lesser curvatures of the stomach are established via the different growth on the left and right sides. Pylorus is tipped superiorly by cranio-caudal rotation. Pyloric sphincter is formed by the proliferation of the mesoderm derived smooth muscle. This smooth muscle lies in the caudal end of the stomach. The stomach is pulled up by the rotation of the stomach and duodenum about a ventrodorsal (A-P) axis. In the 8th week, due to these rotations, the duodenum is pulled into a C-shaped position. Hence the postnatal position for the stomach and duodenum is achieved.

The greater and lesser omenta are formed by the dorsal and ventral mesenteries of the stomach respectively. Also the ventral mesentery is attached to the developing liver. Distinct spaces of the peritoneal cavity is produced by the rotations of the forgut structures and the development of the omenta. The space posterior to the stomach is called the lesser sac or omental bursa. The space anterior to the stomach is called the greater sac. The greater sac is anteriorly inferior to the stomach. A small opening is located near the liver’s hilum which is called the epiploic foramen. The greater and lesser sacs communicate through the epiploic foramen. From 4 layers of peritoneum, a thick sheet is forms via the anterior and posterior folds of the greater omentum fusing.<ref name="PMID16052677"><pubmed>16052677</pubmed></ref>

===Liver, Gallbladder and Bile Duct===

Early in the fourth week of the foregut development, the liver, biliary duct system and gallbladder are seen as ventral outgrowth (hepatic diverticulum). This ventral outgrowth is from the caudal/distal part of the foregut. Hepatic diverticulum is formed via the interaction between bipotential cells and FGF’s which is secreted by the developing heart. There is a mass of splanchnic mesoderm between the midgut and the developing heart. This mass is called septum transversum which is an extension of diverticulum. The ventral mesentry for this region is then formed by the septum transversum.

As the hepatic diverticulum grows in between the layers of ventral mesogastrium, it divides into two parts. Primordium of the liver is the larger cranial part of the hepatic diverticulum. The kupffer cells, fibrous and hematopoietic tissues of the liver are all derived by mesenchyme in the septum transversum.<ref name="PMID23720330"><pubmed>23720330</pubmed></ref>

From the 5th to 10th weeks, the liver grows rapidly and fills the upper abdominal cavity largely. The development and segmentation of the liver is determined by the amount of oxygenated blood flowing from the umbilical vein and into the liver itself. At first, both right and left lobe are of the same size but eventually the right lobe becomes larger. During the 6th week, hematopoiesis begins which gives liver a bright reddish appearance. The liver will account for 10% of the total fetus weight by the ninth week. The bile formation begins during the 12th week. Bile is formed by hepatic cells.

The gall bladder is formed by the small caudal part of the hepatic diverticulum. The cystic duct is formed by the stalk of the diverticulum. The connection between the hepatic and cystic ducts via stalk to the duodenum becomes the bile duct. Initially the bile duct is to the ventral aspect of the duodenum but as the duodenum grows and rotates, the bile duct entrance is carried to the dorsal aspect of the duodenum. After the 13th week, the bile entering the duodenum via bile duct gives the meconium (intestinal contents) a dark green colour.<ref name="PMID23799566"><pubmed>23799566</pubmed></ref>

Ventral mesentery is a thin double layered membrane which gives rise to:
* The lesser omentum passing from the liver to the lesser curvature of the stomach (hepatogastric ligament) and from liver to duodenum (hepatoduodenal ligament)
* Extending from the liver to the ventral abdominal wall is the falciform ligament.

From the umbilical cord to the liver, the umbilical vein passes on the border of falciform ligament. Also the visceral peritoneum of the liver is derived from ventral mesentery which is derived from mesogastrum. The whole liver is covered with peritoneum except the bare area which is in direct contact with the diaphragm.

===Duodenum===

The proximal duodenum if formed by the caudal part of the foregut. Proximal duodenum is supplied by the anterior and posterior branches of the superior pancreaticoduodenal artery. This is a branch of the celiac artery. The duodenum and the pancreas are pushed up against the posterior abdominal wall as the rotation of the stomach takes place. The mesothelium which is covering the duodenum contracts and eventually fuses with the mesothelium covering the posterior abdomen wall. Due to this the duodenum becomes located behind the peritoneum which is known as retroperitoneal. However since the duodenum has not yet began its development in a retroperitoneal position, it is said to be secondary retroperitoneal organ.

During 5th and 6th week of development, the lumen of the duodenum becomes progressively small and occludes. The lumen recanalizes by the end of week 8. If recanalization fails, this results in duodenal stenosis or atresia. Most of the ventral mesentery of the duodenum has disappeared by this time.

===Pancreas===

The ventral pancreatic bud and the dorsal pancreatic bud are two caudal outgrowths from the forming liver. The endoderm develops into branched tubules which are attached to the secretory acini (exocrine pancreas) within each bud. Islet of Langerhans (endocrine pancreas)<ref name="PMID23630303"><pubmed>23630303</pubmed></ref> is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue<ref name="PMID22743232"><pubmed>22743232</pubmed></ref>. This tissue is within the parenchyma of the exocrine glandular tissue.<ref name="PMID15072563"><pubmed>15072563</pubmed></ref>

The ventral and dorsal buds fuse together via the primary rotation of the gut tube which gives a single organ in the adult. The head of the pancreas consist of an uncinated process which is derived from the ventral pancreatic bud. The rest of the head, body and tail of the pancreas are derived from the dorsal pancreatic bud. The distal duct systems of both ventral and dorsal buds join together to form the main pancreatic duct, which drains into the common bile duct. At this site, duodenal papilla is present. Failure for the fusion of buds can lead to annular pancreas.

During the 5th month of development, insulin secretion begins. Along with duodenum, the pancreas is also pressed against the posterior abdominal wall hence becomes a retroperitoneal structure. <ref name="PMID23597482"><pubmed>23597482</pubmed></ref>

==Midgut==
Structures of Midgut:

-Ileum

-Appendix

-Ascending colon

-Hepatic flexure of colon

-Cecum

-Jejunum

-Duodenum (distal half of 2nd part, 3rd and 4th parts)

-Transverse colon (proximal two-thirds)

Nerve supply: Superior mesenteric plexus

Blood Supply: superior mesenteric artery<ref name="PMID24891783"><pubmed>24891783</pubmed></ref>.

===Midgut Rotations (Embryonic)===
Development of the midgut in the embryonic period is characterized by rapid elongation of the gut and its mesentery. The loops of the week 10 intestine position themselves as shown in the hand drawn illustration below is a result of embryonic rotations.

[[File:Human- fetal week 10 sagittal plane D.jpg|thumb|Week 10 Fetus: Note the excessive size of the liver in the abdominal cavity causing midgut herniation]]

===Midgut Herniation===
Herniation of the midgut usually begins around week 5 of the embryonic period. Connected by dorsal mesentery the herniation occurs as a result of the intestine (particularly the ileum) growing faster than the abdominal cavity during this embryonic period. As seen in the table below it is thought that all midgut herniation’s of the fetus should occur by weeks 9-10 <ref name="PMID14745932"><pubmed>14745932</pubmed></ref>.
{| class="wikitable" border="1"
|-
! Week of Gestation
! Percentage of Foetuses Herniated

|-
| 8
| 64% (note: embryo)
|-
| 9
| 100%
|-
| 10
| 100%
|-
| 11
| 25%
|-
| 12
| 0%
|}Table 1.1: Percentage of Herniated midguts during weeks 8-12<ref name="PMID2528908"><pubmed>2528908</pubmed></ref>.

'''Week 10:''' The herniation occurs because of the lack of space in the intra-abdominal cavity mainly due to the large liver and kidneys. As a result the rapidly growing intestinal loops of the midgut are herniated at the umbilicus to accommodate for this lack of space.

[[File:Week 10 Midgut Herniation.png|center|500px]]
Week 10 Herniated Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Retraction of Midgut===
'''Week 11:''' The intestinal loops that have migrated to the umbilicus usually return to the abdominal cavity between 8 and 12 weeks of gestation<ref name="PMID9203209"><pubmed>9203209</pubmed></ref>. This is shown in figure 1.b as now all the intestine is back in the abdominal cavity in comparison to the week 10 fetus whose midgut was still herniated. Although it is not exactly known why the midgut goes back into the abdominal cavity it is thought that the following factors play a major role:

-growth and expansion of the abdominal cavity to cover the herniated midgut

-regression of mesonephric kidney for more space

-reduced growth of the liver for more space<ref name="PMID8345550"><pubmed>8345550</pubmed></ref>

[[File:Week 11 Midgut Herniation.png|center|500px]]
Week 11 Midgut<ref name="PMID2908440"><pubmed>2908440</pubmed></ref>

===Features of Midgut===

'''Peyer's Patches:'''
Peyer's patches are organised lymphoid nodules. By week 30 of gestation the fetal small intestine contains on average 60 peyer's patches<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>. During weeks 15-16 there is a rapid spurt in which the development and maturation of lymphoid follicles of T and B cells allows the continual development of the foci of peyers patches at a continual rate within the small intestine<ref name="PMID2276071"><pubmed>2276071</pubmed></ref>. At week 19 these aggregations mature into recognisable peyer's patches. In week 24 of gestation the patches become macroscopically visible<ref name="PMID18668776"><pubmed>18668776</pubmed></ref>.

'''Interstitial cells of cajal:''' Interstitial cells of Cajal (ICC) are specialised network-forming cells that play important roles in the control of digestive motility. In the small intestine c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal appear in week 9. ICC cells then appear in between weeks 10-12 in the large intestine<ref name="PMID 24414177"><pubmed> 24414177</pubmed></ref>. The ICC cells are only present in the proximal duodenum at the end of the embryonic period in the form of a wide belt of tightly packed cells around the inception of the myenteric plexus ganglia. The ICC cells emerge in the distal duodenum at the beginning of the fetal period in the arrangement of thin rows of pleomorphic cells at the level of the myenteric plexus<ref name="PMID 21352475"><pubmed> 21352475</pubmed></ref>.

'''Villi Formation:''' At week nine in fetal development the small intestine is composed of mesenchyme and pseudo stratified columnar epithelium. Around week 10 small Lumina develop near the base of the epithelium<ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>. Ridges are formed by an elongation of individual epithelial cells. By approximately week 11 these ridges form a longitudinal zig-zag pattern after folding in a concertina fashion. The main lumen is not in balance with the small lumina formed at the base and as a result there is an extension of the small lumina to the main luminal surface and exofoliation of the redundant cells. This leads to a division of the zig-zag folds into primary villi. Therefore the villi can be seen by week 11 in the small intestine<ref name="PMID 507402"><pubmed> 507402</pubmed></ref>. The primary villi trun into secondary villi following the development of cyst like structures within the epithelium to extend the lumen. By week 16 the villi appear throughout the entire intestine. <ref name="PMID 7158824"><pubmed> 7158824</pubmed></ref>

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|300px|thumb|left|Cloaca of human embryo from twenty-five to twenty-seven days old.]]
[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

During embryological development, human gastrointestinal and urinary tract share a common vessel known as the cloaca. By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme, will have formed down the angle between the allantois and hindgut and fuses with the cloacal membrane. This forms an anterior urogenital sinus and a posterior anorectal canal. The anterior portion of the membrane that forms the urogenital membrane is larger than its posterior anal membrane. In Week 9, there is proliferation of the the mesenchyme around the anal membrane raising the surrounding ectoderm, forming the proctodeum (a shallow pit). There are swelling around this pit that are referred to as anal folds. The rectal membrane at the base of the anal pit, soon ruptures to create the anal canal which connects the GIT from the rectum to the amniotic cavity.

The junction between the anal pit ectoderm and hindgut endoderm Is designated by the anatomic anorectal or pectinate (dentate) line, the former site of the anal membrane. This area is where the epithelium changes from columnar to stratified squamous epithelium. This squamous tissue begins to keratinise and becomes continuous with the perineum. Within the hindgut portion, the anal canal is supplied by the inferior mesenteric artery, whereas the anal pit is supplied by the internal pudenal branch of the internal iliac artery

===Colon Development===

During fetal stages, the Colon undergoes lengthening and maturation. After the abdominal cavity has enlarged enough to accommodate all of the Gastrointestinal tract, the return of the herniated small intestines forces the distal end of the colon into its final position in the left side of the peritoneal cavity. the proximal end of the colon returns after the Small intestines, with the cecal end swinging to the right and downwards

* Week 8-12 the intramural ganglia develop<ref name="PMID1232090"><pubmed>1232090</pubmed></ref>

* Week 11: Taeniae Coli and Huastral Clefts begin to appear<ref name="PMID5556677"><pubmed>5556677</pubmed></ref>

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15<ref name="PMID12982018"><pubmed>12982018</pubmed></ref>

* Week 20 intestinal villi formation is completed. incorporates all of the colon as well as the Small intestines<ref name="PMID1214115"><pubmed>1214115</pubmed></ref>

==Abnormalities==

{| class="wikitable mw-collapsible mw-collapsed"
! BEFORE FETAL STAGE
|-
|{{click this red link for further information about disease occuring before fetal stage
| name = Congenital malformations and deformations of digestive system
| title = [[Congenital disorder|Congenital]] malformations and deformations of [[digestive system]] ([[ICD-10 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities#(Q35–Q45) digestive system|Q35–Q45]], [[List of ICD-9 codes 740–759: congenital anomalies#Digestive system|749–751]])
| state = {{{state|autocollapse}}}
| listclass = hlist
| titlestyle = background:Silver
| groupstyle = background:#fd6;
}}<noinclude>
</noinclude>

|}

'''DURING FETAL STAGE'''

'''Cleft Palate'''

Cleft palate is one of the most common congenital birth defects affecting at rates of 75.9 per 100000 births in 2003.<ref name="PMID3960056"><pubmed>3960056</pubmed></ref>. Females are affected with this abnormality more than male at ratio of 2:1 according to studies. It occurs between the 6th and 11th week of fetal development. There is strong data which links to maternal smoking being possible cause of cleft palate in the offspring.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref> Alcohol consumption, solvents and agricultural chemicals have also been seen as possible causes however there are many genetic errors (such as aberrant gene variants) that can possibly lead into cleft palate abnormality making its etiology mostly unknown.<ref name="PMID2825065"><pubmed>2825065</pubmed></ref>

Cleft palate can occur with or without cleft lip. It is a defect of the normal development of soft and hard palate (part of the oral cavity). Cleft of the palate occurs as a result from disruptions that affect cellular migration, proliferation, apoptosis, extracellular matrix deposition and morphogenetic movements.<ref name="PMID0059463"><pubmed>0059463</pubmed></ref> These events are all important in the formation of lip and palate. [[File:Different forms of cleft palate.png|thumb|right|400px|A) Incomplete cleft palate B) unilateral complete cleft lip and palate C) Bilateral complete cleft palate and lip.]]Secondary palate form from the pair of palatal shelves (vertically orientated outgrowths of the maxillary process). The shelves go into a horizontal position just above the tongue by elevating and expanding and then fuse at the midline with each other. When there is disruption/deregulation in any of these processes the shelves are unable to fuse and this is called cleft palate. <ref name="PMID0059463"><pubmed>0059463</pubmed></ref>. Mesenchyme derived from cranial neural crest cells and pharyngeal ectoderms normally interact so that the palate growth and fusion occur. Interruption in the interaction of these two tissues therefore also leads to cleft palate.

Cleft of the palate can either be incomplete, unilateral complete or bilateral complete. Complete cleft means the maximum degree of cleft of any of the types. The image on the right shows the different forms of cleft of the palate (with or without cleft of the lip). The end result of this abnormality leads the roof of the mouth directly connected with nasal cavity.

'''NB: The picture is showing the roof of the mouth with the nose on top, and the lips just below it in pink and oral cavity in red.'''

'''Gastroschisis'''

Gastroschisis is a congenital birth defect which can be diagnosed early in fetal development. It is the most common neonatal abdominal wall defect which occurs equally in males and females. Studies suggest white population is more affected by this abnormality in comparison to Hispanics and dark skinned people.<ref name="PMID11778986"><pubmed>11778986</pubmed></ref> It is a defect of the anterior abdominal wall, usually to the right of the umbilical cord and the peritoneal membrane that normally covers the bowel is absent. The defect involves all layers of the abdominal wall and in this abnormality, an infant’s intestine (small and large intestine) protrude out and into the amniotic fluid. <ref name="PMID">8590188<pubmed>8590188</pubmed></ref>Other organs such as the stomach and liver can also bulge out from the hole and no membrane covers these organs in this abnormality.

Possible cause:

The cause of Gastroschisis is not completely clear however a potential mechanism include tearing at the base of umbilical cord before the umbilical ring closes or the failure of one or more folds in the abdominal wall to fuse completely and in the correct manner. <ref name="PMID11778986"><pubmed>11778986</pubmed></ref>

Due to the failure of the closing as stated above, organs protrude out and the eviscerated bowl is exposed to amniotic fluid for a long period of time, causing mucosal and muscular injury. The organs that remain out of the body wall are also exposed and vulnerable to infection in the open air as an infant is born. In more uncommon cases, chromosomal syndromes such as trisomy 18, 13, or 21 or sex chromosome anomalies have been found in association with Gastroschisis.
In recent findings Gastroschisis has also been seen to be a result from vascular events causing disruption of fetal abdominal wall. For example Maternal vascular under perfusion is a possible underlying cause of intermittent ischemia to the abdominal wall.

'''Omphalocele'''

[[File:GIT 2.jpg|thumb|right|300px|Large omphalocele caused due to failure of the intestine at 10 weeks of development to return to abdominal cavity.]]

Omphalocele is a common midline abdominal wall defect of variable size affecting 2-3 infants per 10,000 births worldwide. <ref name="PMID">4075420<pubmed>4075420</pubmed></ref> It is a feature of the below abnormality (Cloacal Extrophy). It is similar to Gastroschisis however, it is characterised with the absence of fascia, muscle, and skin and occurs due to a defect in the development of the muscles in the abdominal wall.<ref name="PMID">222976993<pubmed>22976993</pubmed></ref> A fetus with omphalocele tends to have herniation of abdominal contents into the base of the umbilical chord. A membranous sac that has amnion and peritoneum covers these contents lying within the umbilical chord. Omphalocele in the later stage of fetal development (approximately week 11) occurs after normal infolding of the embryo therefore having formed an abdominal cavity. When the umbilical ring does not close around the umbilical cord then this small defect occurs containing only the intestine.<ref name="PMID">2960962<pubmed>2960962</pubmed></ref>

===Anorectal deformities===

There are 3 major types of anorectal deformities that can be found clinically

- imperforate anus (abscent): the rectal membrane doesn’t rupture leaving Gastrintestinal tract to be completely or incompletely walled off from the outside. All varieties of this deformity require immediate surgical intervention at birth

- Insufficient anus leads to problems of meconium evacuation and should be treated without delay

- Ectopic sinus: does allow some intestinal transport, but is usually functionally insufficient

'''Cloacal Extrophy'''

If the cloaca ruptures before completely partitioning, it can lead to extrophy. Although extremely rare with only occuring in one in 200 000-400 000 births, it requires immediate surgical attention postnatal <ref name="PMID12651743"><pubmed>12651743</pubmed></ref>. It arises from the failure of the caudal fold to close. Cloacal extrophy results in a child being born with with many inner-abdominal structures exposed. A portion of the large intestine lies outside of the body, and on either side of it are the two halves of the bladder. To diagnose this, MRI Imaging is usually performed during development to detect the 'elephant trunk sign' of cloacal extrophy<ref name="PMID22878705 "><pubmed>22878705</pubmed></ref>

[[File:383 2012 3133 Fig2 HTML.jpg|thumb|right|600px|MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)]]

'''Superficial anorectal deformities;''' <ref name="PMID23073994"><pubmed>23073994</pubmed></ref>

• Anal agenesis or insufficient anus (with or without fistula):
• Membranous atresia or covered anus (with or without fistula
• Anorectal agenesis with or without fistula

'''Deep deformities:'''

• Pure rectal atresia: complete failure of the formation of the inferior part of the rectum and anal canal
• Rectal atresia with fistula: always insufficient. The length and degree of anastomosis differentiate the various types of anomaly

'''Mixed deformities'' '
include all forms of ectopic anus

• May involve abnormal anastomoses of the anus to the perineum and reflect both perineal and cloacal abnormalities

'''Hirschsprung disease'''

Hirschsprung disease is congenital disease that affects 1 in 5000 live births and has a male dominance over female with a ratio of 4:1.<ref name="PMID23528997"><pubmed>23528997</pubmed></ref>

The gastrointestinal tract derives from endoderm extending from mouth to anus. The function of the GIT depends on the enteric nervous system. Neurons and Glia of enteric nervous system are organised into ganglia. This abnormality is characterised when there is a congenital absence of these neurons in the distal colon (part of Hindgut) of the GIT. The absence of neuron can be due to disrupt in normal migration, proliferation, differentiation, survival or apoptosis of neural crest cells which occurs between the 5th and 12th week of gestation. <ref name="PMC3691347"><pubmed>PMC3691347</pubmed></ref>

Certain mutation in genes such as GFRα1, NRTN, EDNRB,PHOX2b, SOX10, and SHH have been thought to play a part in the pathogenesis however it is not fully understood. <ref name="PMID">1683643<pubmed>1683643</pubmed></ref> Due to this disease the normal function of the Hindgut does not proceed this includes movement such as peristalsis.<ref name="PMC1683643"><pubmed>PMC1683643</pubmed></ref>

<pubmed>4075420<pubmed/>

<pubmed>23553304<pubmed/>

<pubmed>2960962<pubmed/>

'''Abnormalities that can occur in GIT system during fetal development'''

'''List of research/articles:'''

1.<pubmed>22777173</pubmed>

<ref>Charles D. Bluestone M.D., Roy Kerry M.D. andWilliam K. Sieber M.D,2009,January,Congenital esophageal stenosis†‡,The Laryngoscope,volume79,issue 6,1095–1104,http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1288/00005537-196906000-00004/pdf}}</ref>

==References==
<references/>