Embryology - User contributions [en-gb]

User:Z3375627

2014-10-29T00:10:51Z

Z3375627: /* Lab Attendance */

{{StudentPage2014}}

=Online Assessment=
==Lab 1==
===Article 1===
[http://www.ncbi.nlm.nih.gov/pubmed/24520460 PMID24520460]

<<pubmed>24520460</pubmed>>
'''method & findings'''
women aged 20 to 29 with homogenous characteristics of basal hormone levels, duration of infertility, Body mass index, antral follicle count and age were split into 4 groups of differing endometrial wall thickness (1 <7mm, 2 7-10mm, 3 10-14, 4 >14mm). thickness was measure using TV- USG in the midsagittal plane on the day of hCG administration when 1 or 2 follicles reached 17mm in size. 35-36 hours following hCG for final maturation, TV- USGguided needle aspiration of the follicular fluid was carried out, as was ICSI in all cases. Luteal phase was supported on the oocyte "pick-up" day until serum pregnancy test 12 days later. Clinical pregnancy could be confirmed by presence of fetal sac or fetal cardiac activity 2 weeks later via ultrasound.

The article found that of the women in group 1 (endometrial wall = <7mm) there was a dramatic reduction in Implantation rate, CPR, and ongoing pregnancy rate (OPR)compared to group 2, 3 and 4. There didnt seem to be a significant difference between 2, 3, and 4 in this catagory of result. Retrieved oocyte number, transferred embryo number, and the fertilization, cleavage, and implantation rates (IR) was also found to be similar in all four groups. Results then showed that women of an endometrial wall thickness of less than 7mm would experience a significantly lower clinical pregnancy rate (although no threshold was observed)
===Article 2===
[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879877/ PMID3879877]

<<pubmed>PMC3879877</pubmed>>
'''method & findings'''
Seminal plasma concentrations of pH, total Calcium, ionized calcium, and inorganic phosphate were recorded in 80 male patients to find a correlation of the substances to mobility and spermatazoa count. The 31 patients who were recorded as having hypomotility (<60%) exhibited lower calcium concentrations (0.19+0.01mmol/L) compared with the normal motility group ( 0.24+0.01mmol/L). The same was observed with phosphate levels (hypo= 5.64+1.62mmol/L normal= 7.83+1.27 ). No noticable differences were observed in the pH levels betweeen the two groups. Of those in the hypomotile group, there was a greater occurance of abnormal form in the spermatazoa, 36% compared to the normal groups 5%. The mobility and count of the spermatazoa was performed using a binocular microscope and improved neubauer counting chamber.

The article shows that there was a relationship between calcium and phosphate levels that indicate that lower levels of the two in seminal fluid would result in lower count and motility as well as presence of abnormal forms in the spermatazoa. There did seem to be a paradoxical effect from calcium levels on sperm depending the maturation level of the sperm. In the epididymis, calcium ion stimulate immature sperm whereas in ejaculated semen, it inhibits sperm motility.

--[[User:Z8600021|Mark Hill]] These are useful references and descriptions, fix the reference formatting. (5/5)

==lab 2==
[[File:P63_staining_of_human_anorectum_in_10th_week.jpg]]

P63 staining of human anorectum in the 10th week. There was considerable proliferation activity within the epithelia of rectum and anal canal. The P63 immunoreaction still remained strongly immunoreactive on the epithelium of the anal canal while the rectum exhibited no reaction<ref><pubmed>23736768</pubmed>| [http://www.ncbi.nlm.nih.gov/pubmed/23736768]</ref>
<references/>

--[[User:Z8600021|Mark Hill]] This is a relevant image, you need to fix the associated information formatting on the file summary page and include the student image template. (4/5)

==Lab 3==
'''Hindgut development during the human fetal stages'''

1.<pubmed>10716947</pubmed>
2.<pubmed>12171973</pubmed>
3.<pubmed>23073994</pubmed>

--[[User:Z8600021|Mark Hill]] These are 3 references, where is a single sentence describing why you have selected these for the project? (4/5)

==Lab 4==
'''Identify a paper that uses cord stem cells therapeutically and write a brief (2-3 paragraph) description of the paper's findings.'''
[http://www.ncbi.nlm.nih.gov/pubmed/21939170 PMID21939170]

<<pubmed>21939170</pubmed>>

Research was conducted into the ability for a non-haematopoietic population of Mesenchymal stem cells (MSC) within adult bone marrow to inhibit the poliferation of tumour cells. Bone marrow was aquired and dilated with 1X PBS (phosphate buffered saline and prepared for immunophenotyping using a FACSCaliber flow cytometer and then stained.

Introduced to BV173 Tumour cells (a human B cell precursor leukemia). After an incubation period of 18hours in 37°C, these cells were harvested and thymidine incorporation was
measured by liquid scintillation spectroscopy. An inhibitory effect pronounced when there is a direct cell to cell contact. The cell cycle analysis
revealed a substantial
reduction in DNA synthesis in presence of MSC arresting tumour cell proliferation in G0/G1 phase of cell cycle. This prevented the tumour cells to enter into S phase of cell cycle.

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

:*The foramen ovale - An opening in the interatrial septum allowing some blood to bypass the pulmonary circuit by passing from the right atrium directly to the left atrium. Postnatal, this fuses shut to leave the fossa ovale

:*The ductus arteriosus - A short, muscular vessel that connects the pulmonary artery to the descending aorta allowing the blood that didnt pass through the foramen ovale to bypass pulmonary circulation.. Ligamentum arteriosum is the remnant after postnatal closure.

:*The ductus venosus – Shunts blood from the umbilical vein to the inferior vena cava, bypassing the fetal liver and delivering oxygenated blood from the placenta to the fetal heart. Ligamentum venosum is the remnant after postnatal closure.

==Lab 5==

Cloacal Extrophy

By the end of week seven, the urorectal septum, a coronal ridge of mesenchyme has 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.

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 [19]. 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

<pubmed>22878705</pubmed>

==Lab 6==
Group work

==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.'''

A study was done into the role of molecules that modulate the differentiation and proliferation of pancreatic endocrine cells. during embryonic development, the glucagon cells that co-expressed tyrosine hydroxylase rarely proliferated and didn't express precurser marker neurogenin. There was also seen to be a increased expression of the transcriptional repressor Hes1. The study indicates that this finding may have important implications for approaches seeking to promote the generation of beta cells to treat diabetes.

<pubmed>25082160</pubmed>

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

Embryonic layers are the ectomesenchymal cells, the ectoderm of the first pharyngeal arch, and neural crest. Tissues involved are the Ameloblasts and Odontoblasts. Odontoblasts forms predentin which calcifies to form dentin and are Mesenchymal cells derived from the neural crest cells that differentiate under the influence of enamel epithelium. Ameloblasts Produce the enamel during the ossification of the jaw

==Lab 9==
'''Group 1'''

Overall this is a well produced project so far, very impressed. Only minor changes to polish up some sections are needed. The introduction help with orientating the reader with the content especially with the origins of development and brief on how fetal compares with embryonic stages as well as conducting and respiratory side of lung function. The project as a whole is not text heavy with some good images included which again are helpful in guiding the information

The tables and placement of content is very well thought out with the exception of referencing. It would be advisable to move all the references to one spot (preferably the end) so content isn't so broken between sections. viewers looking for the references can follow those link you've provided wherever they end up.

Pictures, while a good addition to supplement the text information, need to have more information regarding the individual images. some text highlighting what the viewer is looking at in the image will be beneficial

some sections need more work in them. Abnormalities is looking good (but i'm sure will improve), but other sections like Current models and historic findings needs to have more research with integrated referencing

'''Group 2'''

Good introduction with integrated citations. Content is easy to understand and well presented. There needs to be more references in some sections like development to compare with the rest of the work, which is well done.

Obviously historic findings needs to have some content added

Timeline is simple and easily gives information on sections

As a whole, the project feels like a wall of text even with the images included. breaking some sections up to more concise, dot pointed content could do well.

more work needs to be done tidying up referencing. Changing the references so that they link to a list at the end would be a good idea. You can always look at other project pages and just copy the reference style

Images are well used throughout the project. Again, relocating the references for these would be a good idea. A few have no flavour text to identify what the viewer is looking at. Look at adding this to page.

That all being said, well thought out and executed project so far

'''Group 4'''

Nice amount of content on this page. some work needs to go in reformatting the development and Current model sections as the dot points don't bring some of the information across effectively. Perhaps a table could remedy some parts

The Table included is well done but could use some references integrated.

Referencing is very poor in the development and current research sections. more work needs to be done here in not only obtaining more citations for the content as there is next to none for the amount of content, some reformatting needs to be done so the citations are all listed in the same spot

A few points where information is missing as per your edits. just make sure to remedy this and proof read before submission to add relevent content or remove the text.

Great work so far. More images can't hurt

'''Group 5'''

Introduction should be more to do with the content rather than the intention of the page. Introduce the reader to the system and then go into development in the next sections.

Fantastic job on the overview with the table being a highlight of this project

All of the images are very well integrated and presented. good work on the text and also the referencing in abnormalities section.

More references need to be included within text. Low amount thus far. References also need to be reformatted to be listed in one spot. You can always look at other groups page and copy their layout. The abnormalities section on your page has the right idea. Have a chat in group about it.

The main issues with this project are mainly formatting, very well done otherwise

'''Group 6'''

Introduction needs to have content in it. Start with a quick orientation to the system that you are presenting with some key points on development and structures.

Tables in Pineal gland section needs some work, adding informationn and keeping them cited.

References need to be collated in one spot. look at other groups content and copy their style and use it to declutter your page.

The images that you are using are good, but more need to be added to areas that are lacking them.

Still a lot of text indicating work that needs to be done. I'm sure you will get around to fixing this, but just make sure to proof read your own content to not miss any. Same work to be done rewording some of the subheading texts. try to avoid rhetorical questions like in the timelines

There are timelines scattered throughout the project page. Moving them all to one section near the top, perhaps under the introduction would help to give an overview of all the content

The section formatting is very good with a nice amount of information. Only thing lacking there is some more in text citations.

Great work so far

'''Group 7'''

Nice introduction. Short and to the point

Images are well used but there needs to be more. content is too text heavy so far. even if you recreate some images yourself, it would help the page greatly

Needs more references for the text heavy sections, even if you are reusing the same reference, we need to see where the information came from. References also need to be collated in one spot. look at other groups content and copy their style and use it to declutter your page.

There are sections missing content like spinal cord, meninges and abnormalities. Make sure to go through all your content to not miss these parts by submission.

Some information on the current research rather than just citing the research needs to be done. reduce the reference and add more info.

Good work, some minor formatting and will look great.

'''Group 8'''

All Text and no images. Not a good look to go through. some formatting of the text would be a good idea to break up the text in addition to adding images.

The referencing is well done for the content at the top of the page. Whoever is doing the tendon section onward needs to take note of this and add all their references in the same style.

The humour section is unnecessary "information" that i doubt needs to be there. definately consider removing.

The information you have here is good. It will require a lot of work to get it to a point that it is well presented. I understand that it will be difficult with only the two of you in the group. Just keep adding a little bit each day to the sections.

=Lab Attendance=
:*Lab 1 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:51, 6 August 2014 (EST)
:*Lab 2 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 11:45, 13 August 2014 (EST)
:*Lab 3 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:09, 20 August 2014 (EST)
:*Lab 4 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:27, 27 August 2014 (EST)
:*Lab 5 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 13:05, 3 September 2014 (EST)
:*Lab 6 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:48, 10 September 2014 (EST)
:*Lab 7 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:06, 17 September 2014 (EST)
:*Lab 8 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 11:41, 24 September 2014 (EST)
:*Lab 9 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 11:17, 8 October 2014 (EST)
:*Lab 10 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:03, 15 October 2014 (EST)
:*Lab 11 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 12:08, 22 October 2014 (EST)
:*Lab 12 --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 11:10, 29 October 2014 (EST)

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

2014 Group Project 3

2014-10-24T07:28:12Z

Z3375627: /* 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 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

2014-10-24T05:11:44Z

Z3375627: /* 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===

'''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|right|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.
|-
| 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

2014-10-24T04:51:57Z

Z3375627: /* 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===

'''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="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

2014-10-24T04:49:03Z

Z3375627: /* 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===

'''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 where the first interpreted process of digestion as a chemical mechanism was discovered through the study of gastric juices
|-
| 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="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/>

File:Cloacal extrophy.jpg

2014-10-24T04:23:24Z

Z3375627:

2014 Group Project 3

2014-10-24T04:19:52Z

Z3375627: /* Hindgut */

{{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

2014-10-24T03:44:37Z

Z3375627: /* Abnormalities */

{{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===

Recent 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

2014-10-24T03:37:40Z

Z3375627: /* Historic Findings */

2014 Group Project 3

2014-10-24T02:56:55Z

Z3375627: /* Historic Findings */

{{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===

Recent 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>

|-
| 1999 || blank blank

|}

==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>

'''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

2014-10-24T02:49:26Z

Z3375627: /* Historic Findings */

{{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===

Recent 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>

|-
| 1999 || blank blank

==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>

'''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/>

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Z3375627:

2014 Group Project 3

2014-10-24T01:07:05Z

Z3375627: /* Abnormalities */

{{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===

Recent 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===

==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>

'''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

2014-10-24T01:01:21Z

Z3375627: /* Foregut */

{{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===

Recent 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===

==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>

'''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

2014-10-24T00:57:29Z

Z3375627: /* Timeline */

{{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===

Recent 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===

==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)===
[[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>

'''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

2014-10-24T00:53:20Z

Z3375627: /* Timeline */

{{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 the 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===

Recent 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===

==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)===
[[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>

'''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

2014-10-24T00:38:51Z

Z3375627: /* Midgut */

{{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'''

[[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===

Recent 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===

==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)===
[[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>

'''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

2014-10-24T00:34:28Z

Z3375627: /* 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'''

[[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===

Recent 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===

==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.<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>

'''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

2014-10-24T00:28:48Z

Z3375627: /* Current Research, Models and Historic Findings */

{{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'''

[[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===

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.<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>

'''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

2014-10-24T00:24:07Z

Z3375627: /* Hindgut */

{{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|500px|thumb|right|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.<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>

'''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

2014-10-24T00:22:19Z

Z3375627: /* Current Models */

{{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|500px|thumb|right|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.<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>

'''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

2014-10-24T00:17:08Z

Z3375627: /* Cloaca partitioning */

{{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.<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>

'''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

2014-10-24T00:09:11Z

Z3375627: /* Cloaca partitioning */

{{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.

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{|
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===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>.

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===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.<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

===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>

'''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

2014-10-24T00:05:58Z

Z3375627: /* Hindgut */

{{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.<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

===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>

'''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:Cloacal partition completed.png

2014-10-23T23:40:05Z

Z3375627:

Tail end of human embryo; from eight and a half to nine weeks old.

This faithful reproduction of a lithograph plate from Gray's Anatomy, a two-dimensional work of art, is not copyrightable in the U.S. as per Bridgeman Art Library v. Corel Corp.; the same is also true in many other countries, including Germany. Unless stated otherwise, it is from the 20th U.S. edition of Gray's Anatomy of the Human Body, originally published in 1918 and therefore lapsed into the public domain.
-----
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:Urorectal septum.png

2014-10-23T23:37:43Z

Z3375627:

Cloaca of human embryo from twenty-five to twenty-seven days old.

This faithful reproduction of a lithograph plate from Gray's Anatomy, a two-dimensional work of art, is not copyrightable in the U.S. as per Bridgeman Art Library v. Corel Corp.; the same is also true in many other countries, including Germany. Unless stated otherwise, it is from the 20th U.S. edition of Gray's Anatomy of the Human Body, originally published in 1918 and therefore lapsed into the public domain.

-----
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:Cloacal extrophy.jpg

2014-10-23T23:36:38Z

Z3375627:

MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)<ref name="PMID22878705"><pubmed>22878705</pubmed></ref>.

<references/>

This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
-----
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:Cloacal extrophy.jpg

2014-10-23T23:35:06Z

Z3375627:

MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)<ref name="PMID22878705"><pubmed>22878705</pubmed></ref>.

<references/>

[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]])
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

2014 Group Project 3

2014-10-23T23:31:21Z

Z3375627: /* Anorectal deformities */

{{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: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>

'''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:Cloacal extrophy.jpg

2014-10-23T23:27:41Z

Z3375627: MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)<ref name="PMID22878705"><pubmed>22878705</pubmed></ref>. ~~~ This article is distributed under the terms of the Creative Common...

MRI of Cloacal extrophy during fetal development showing omphalocele (a), neural tube defect (b) and bladder exstrophy (c)<ref name="PMID22878705"><pubmed>22878705</pubmed></ref>.

[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]])
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Talk:2014 Group Project 3

2014-10-23T12:06:00Z

Z3375627: /* Discussion */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
{| class="wikitable mw-collapsible mw-collapsed"
! Reviews
|-
| 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.

-----

*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!!

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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.

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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.

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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.
----
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.

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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)

Yeah, looks good [[User:Z3415141|Z3415141]]. Everything is coming along nicely. I may fiddle with the picture layout in the Midgut section when I edit tomorrow just to make the whole page a little more uniform and condense. If anyone wants anything specificly changed done let me know below, I'll be working on the page until roughly 3-4pm tomorrow --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 23:01, 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>

Talk:2014 Group Project 3

2014-10-23T12:01:02Z

Z3375627: /* Discussion */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
{| class="wikitable mw-collapsible mw-collapsed"
! Reviews
|-
| 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!!

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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.

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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.

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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.

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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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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)

Yeah, looks good [[User:Z3415141|Z3415141]]. Everything is coming along nicely --[[User:Z3375627|Z3375627]] ([[User talk:Z3375627|talk]]) 23:01, 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>

Talk:2014 Group Project 3

2014-10-23T12:00:42Z

Z3375627: /* Discussion */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
{| class="wikitable mw-collapsible mw-collapsed"
! Reviews
|-
| 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.

----

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!!

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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.

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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.

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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.

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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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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.

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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.

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==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)

Yeah, looks good [[User:Z3415141|Z3415141]]. Everything is coming along nicely

==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

2014-10-23T11:52:07Z

Z3375627: /* Features of Midgut */

{{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>

===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

2014-10-22T13:29:12Z

Z3375627: /* Hindgut */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T13:26:38Z

Z3375627: /* Gastrointestinal System */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T13:23:54Z

Z3375627: /* Hindgut */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T13:21:40Z

Z3375627: /* Colon Development */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T13:08:39Z

Z3375627: /* Colon Development */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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

*

* 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 the development intestinal villi formation is completed incorporating the colon as well as the Small intestines

*

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T13:05:06Z

Z3375627: /* Colon Development */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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

*

* Circular Muscle in Large intestines form in Week 8 and Longitudinal muscle formed in Week 12-15

*Week 20 the development intestinal villi formation is completed incorporating the colon as well as the Small intestines

*

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T12:48:53Z

Z3375627: /* Colon Development */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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 it's final position in the left side of the peritoneal cavity.

Week 20 the development if villi is completed and incorporates the colon as well

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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

2014-10-22T12:41:42Z

Z3375627: /* Discussion */

{{ANAT2341Project2014discussionheader}}
==Peer Reviews==
{| class="wikitable mw-collapsible mw-collapsed"
! Reviews
|-
| 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)

==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

2014-10-22T12:24:01Z

Z3375627: /* Hindgut */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T12:18:10Z

Z3375627: /* Cloaca partitioning */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T12:12:35Z

Z3375627: /* Hindgut */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or 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.]]

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.

[[File:Cloacal_partition_completed.png|300px|thumb|right|Tail end of human embryo; from eight and a half to nine weeks old.]]

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

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>

2014 Group Project 3

2014-10-22T12:08:37Z

Z3375627: /* Hindgut */

{{ANAT2341Project2014header}}

=Gastrointestinal System=

==GIT system Overview ==

The GIT system is a complicated system that extends from the Esophagus of the mouth to the anal canal of the hind-gut. Its function is to ultimately turn food that is eaten into energy. GIT (Gastrointestinal Tract) consist of the Fore-gut, Mid-gut and Hind-gut. Majority of the organs are located in the fore-gut. This includes the stomach, duodenum, Liver, pancreas and the spleen. The mid-gut 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 mid-gut is complete, it starts to herniate at beginning of week 6 and continues to do so till week 10. Hind-gut 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 hind-gut instead it gets pushed to the left side by mid-gut during development.

==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]

'''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 )

===Current Models===

'''Fetal Colonic 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. 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>.

===Current Reseach===

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). 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="PMID3024424"><pubmed>3024424</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) is formed by stem cells at the duct branch points. This then develops into discrete islands of vascular endocrine tissue. This tissue is within the parenchyma of the exocrine glandular tissue.

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.

==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 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. 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>.

==Hindgut==

The hindgut consists of the following organ/structures:

*Distal transverse colon

*Descending colon

*Sigmoid Colon

*Rectum (or Cloaca before urogenital partitioning)

Innervation: inferior mesenteric plexus

Blood supply: inferior mesenteric artery

===Cloaca partitioning===

[[File:Urorectal_septum.png|200px|thumb|Center|Cloaca of human embryo from twenty-five to twenty-seven days 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.

[[File:Cloacal_partition_completed.png|200px|thumb|Left|Tail end of human embryo; from eight and a half to nine weeks old.]]

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

==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="PMID1769721214000883"><pubmed>1769721214000883/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. 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.
[[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.]]

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'''

Definition:

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. 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. 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'''

Definition/overview
[[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 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="PMID">3691347<pubmed>3691347</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="PMID">3691347<pubmed>3691347</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.

<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/>