Talk:Gastrointestinal Tract - Intestine Development

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Cite this page: Hill, M.A. (2021, May 9) Embryology Gastrointestinal Tract - Intestine Development. Retrieved from


Gredler ML, Patterson SE, Seifert AW & Cohn MJ. (2020). Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh. Dev. Biol. , 465, 23-30. PMID: 32645357 DOI.

Foxa1 and Foxa2 orchestrate development of the urethral tube and division of the embryonic cloaca through an autoregulatory loop with Shh

Congenital anomalies of external genitalia affect approximately 1 in 125 live male births. Development of the genital tubercle, the precursor of the penis and clitoris, is regulated by the urethral plate epithelium, an endodermal signaling center. Signaling activity of the urethral plate is mediated by Sonic hedgehog (SHH), which coordinates outgrowth and patterning of the genital tubercle by controlling cell cycle kinetics and expression of downstream genes. The mechanisms that govern Shh transcription in urethral plate cells are largely unknown. Here we show that deletion of Foxa1 and Foxa2 results in persistent cloaca, an incomplete separation of urinary, genital, and anorectal tracts, and severe hypospadias, a failure of urethral tubulogenesis. Loss of Foxa2 and only one copy of Foxa1 results in urethral fistula, an additional opening of the penile urethra. Foxa1/a2 participate in an autoregulatory feedback loop with Shh, in which FOXA1 and FOXA2 positively regulate transcription of Shh in the urethra, and SHH feeds back to negatively regulate Foxa1 and Foxa2 expression. These findings reveal novel roles for Foxa genes in development of the urethral tube and in division of the embryonic cloaca.

Kostouros A, Koliarakis I, Natsis K, Spandidos DA, Tsatsakis A & Tsiaoussis J. (2020). Large intestine embryogenesis: Molecular pathways and related disorders (Review). Int. J. Mol. Med. , , . PMID: 32319546 DOI.

Large intestine embryogenesis: Molecular pathways and related disorders (Review)

The large intestine, part of the gastrointestinal tract (GI), is composed of all three germ layers, namely the endoderm, the mesoderm and the ectoderm, forming the epithelium, the smooth muscle layers and the enteric nervous system, respectively. Since gastrulation, these layers develop simultaneously during embryogenesis, signaling to each other continuously until adult age. Two invaginations, the anterior intestinal portal (AIP) and the caudal/posterior intestinal portal (CIP), elongate and fuse, creating the primitive gut tube, which is then patterned along the antero‑posterior (AP) axis and the radial (RAD) axis in the context of left‑right (LR) asymmetry. These events lead to the formation of three distinct regions, the foregut, midgut and hindgut. All the above‑mentioned phenomena are under strict control from various molecular pathways, which are critical for the normal intestinal development and function. Specifically, the intestinal epithelium constitutes a constantly developing tissue, deriving from the progenitor stem cells at the bottom of the intestinal crypt. Epithelial differentiation strongly depends on the crosstalk with the adjacent mesoderm. Major molecular pathways that are implicated in the embryogenesis of the large intestine include the canonical and non‑canonical wingless‑related integration site (Wnt), bone morphogenetic protein (BMP), Notch and hedgehog systems. The aberrant regulation of these pathways inevitably leads to several intestinal malformation syndromes, such as atresia, stenosis, or agangliosis. Novel theories, involving the regulation and homeostasis of intestinal stem cells, suggest an embryological basis for the pathogenesis of colorectal cancer (CRC). Thus, the present review article summarizes the diverse roles of these molecular factors in intestinal embryogenesis and related disorders. PMID: 32319546 DOI: 10.3892/ijmm.2020.4583


Radial WNT5A-Guided Post-mitotic Filopodial Pathfinding Is Critical for Midgut Tube Elongation

Dev Cell. 2018 Jul 16;46(2):173-188.e3. doi: 10.1016/j.devcel.2018.06.011.

Wang S1, Cebrian C2, Schnell S3, Gumucio DL4.

Abstract The early midgut undergoes intensive elongation, but the underlying cellular and molecular mechanisms are unknown. The early midgut epithelium is pseudostratified, and its nuclei travel between apical and basal surfaces in concert with cell cycle. Using 3D confocal imaging and 2D live imaging, we profiled behaviors of individual dividing cells. As nuclei migrate apically for mitosis, cells maintain a basal process (BP), which splits but is inherited by only one daughter. After mitosis, some daughters directly use the inherited BP as a "conduit" to transport the nucleus basally, while >50% of daughters generate a new basal filopodium and use it as a path to return the nucleus. Post-mitotic filopodial "pathfinding" is guided by mesenchymal WNT5A. Without WNT5A, some cells fail to tether basally and undergo apoptosis, leading to a shortened midgut. Thus, these studies reveal previously unrecognized strategies for efficient post-mitotic nuclear trafficking, which is critical for early midgut elongation. KEYWORDS: Wnt5a; apical link; apoptosis; basal process; cell division; filopodial extension; interkinetic nuclear migration; midgut elongation; pseudostratified epithelium; small intestine Comment in Cellular Dynamics Driving Elongation of the Gut. [Dev Cell. 2018] [1]

Topographical anatomy of the intestines during in utero physiological herniation

Clin Anat. 2018 May;31(4):583-592. doi: 10.1002/ca.22996. Epub 2017 Nov 28.

Cho BH1, Kim JH2, Jin ZW3, Wilting J4, Rodríguez-Vázquez JF5, Murakami G6.


Because most malrotations of the small intestine are thought to occur during repackaging, the location of the intestine should vary less during physiological herniation than afterward. Examination of serial sagittal sections of 27 embryos and fetuses (gestational age 6-9 weeks; crown-rump length 15-45 mm) during herniation showed that the jejunum and ascending colon passed through a small opening of the hernia sac at the levels of the stomach and pancreas in 16 specimens. Below the pancreas, a definite mesentery extended between the ascending and descending colon in the abdominal cavity. In the other 11 specimens, the descending colon passed through an opening of normal size and ran posteriorly along the urinary bladder, so the entire ilium, ascending colon, and transverse colon entered the sac. In these specimens, the duodenojejunal junction was usually situated in a window of the mesentery of the colon (internal herniation). The descending colon was observed at an outside location more frequently in earlier specimens. In contrast to our working hypothesis, the locations of the intestine were abnormal in 40.7% (11/27) of samples. In addition, no abnormal colon was observed in any of the seven specimens after repackaging. An outside location of the descending colon was not directly associated with malrotation because recovery was likely. However, the delayed development of the inferior mesenteric arterial branches could cause failure, including death in utero, during or after the repackaging associated with physiological herniation. Clin. Anat. 31:583-592, 2018. © 2017 Wiley Periodicals, Inc. KEYWORDS: colon; human embryos; malrotation; physiological herniation; repackaging PMID: 29044646 DOI: 10.1002/ca.22996

Growth of the colon and rectum throughout gestation: evaluation with fetal MRI

Acta Radiol Open. 2018 Mar 4;7(3):2058460118761206. doi: 10.1177/2058460118761206. eCollection 2018 Mar.

Ben-Nun MS1,2, Ben-Shlush A1, Raviv Zilka L1,2.


BACKGROUND: Congenital abnormalities of the gastrointestinal tract are increasingly being evaluated by prenatal magnetic resonance imaging (MRI). However, there is a paucity of reports describing the normal quantitative development of the fetal colon and rectum on MRI. PURPOSE: To provide growth curves of the MRI estimated diameter of the fetal colon and rectum as a function of gestational age. MATERIAL AND METHODS: This is a retrospective review of 191 singleton fetal MRI studies at 25-39 weeks of gestation. Measurements included maximal diameter of the ascending, transverse, and descending colon on coronal and sagittal views, maximal diameter of the rectum on coronal and sagittal views, and maximal diameter of the rectum at the level of the bladder base on sagittal views. Median growth curves were built using a generalized additive model. Confidence regions were built for 10th, 25th, 75th, and 90th percentiles. RESULTS: Smoothed growth curves for the median, and one and three quartiles for each of the five sections as a function of gestational age were calculated. All graphs had a slightly exponential curve. CONCLUSION: This study provides normal ranges of the prenatal colon and rectum as a function of gestational age. They may serve as reference values when interpreting fetal MRI. KEYWORDS: Fetus; MRI; colon; development; growth; magnetic resonance imaging PMID: 29531795 PMCID: PMC5843125 DOI: 10.1177/2058460118761206


The Digestive Tract and Derived Primordia Differentiate by Following a Precise Timeline in Human Embryos Between Carnegie Stages 11 and 13

Anat Rec (Hoboken). 2016 Apr;299(4):439-49. doi: 10.1002/ar.23314. Epub 2016 Jan 30.

Ueno S1, Yamada S1,2, Uwabe C2, Männer J3, Shiraki N1, Takakuwa T1.


The precise mechanisms through which the digestive tract develops during the somite stage remain undefined. In this study, we examined the morphology and precise timeline of differentiation of digestive tract-derived primordia in human somite-stage embryos. We selected 37 human embryos at Carnegie Stage (CS) 11-CS13 (28-33 days after fertilization) and three-dimensionally analyzed the morphology and positioning of the digestive tract and derived primordia in all samples, using images reconstructed from histological serial sections. The digestive tract was initially formed by a narrowing of the yolk sac, and then several derived primordia such as the pharynx, lung, stomach, liver, and dorsal pancreas primordia differentiated during CS12 (21-29 somites) and CS13 (≥ 30 somites). The differentiation of four pairs of pharyngeal pouches was complete in all CS13 embryos. The respiratory primordium was recognized in ≥ 26-somite embryos and it flattened and then branched at CS13. The trachea formed and then elongated in ≥ 35-somite embryos. The stomach adopted a spindle shape in all ≥ 34-somite embryos, and the liver bud was recognized in ≥ 27-somite embryos. The dorsal pancreas appeared as definitive buddings in all but three CS13 embryos, and around these buddings, the small intestine bent in ≥ 33-somite embryos. In ≥ 35-somite embryos, the small intestine rotated around the cranial-caudal axis and had begun to form a primitive intestinal loop, which led to umbilical herniation. These data indicate that the digestive tract and derived primordia differentiate by following a precise timeline and exhibit limited individual variations. © 2016 Wiley Periodicals, Inc. KEYWORDS: derived primordial; development; digestive tract; human embryo; timeline

PMID 26995337


The growth pattern of the human intestine and its mesentery

BMC Dev Biol. 2015 Aug 22;15:31. doi: 10.1186/s12861-015-0081-x.

Soffers JH1, Hikspoors JP2, Mekonen HK3, Koehler SE4, Lamers WH5,6.


BACKGROUND: It remains unclear to what extent midgut rotation determines human intestinal topography and pathology. We reinvestigated the midgut during its looping and herniation phases of development, using novel 3D visualization techniques. RESULTS: We distinguished 3 generations of midgut loops. The topography of primary and secondary loops was constant, but that of tertiary loops not. The orientation of the primary loop changed from sagittal to transverse due to the descent of ventral structures in a body with a still helical body axis. The 1st secondary loop (duodenum, proximal jejunum) developed intraabdominally towards a left-sided position. The 2nd secondary loop (distal jejunum) assumed a left-sided position inside the hernia before returning, while the 3rd and 4th secondary loops retained near-midline positions. Intestinal return into the abdomen resembled a backward sliding movement. Only after return, the 4th secondary loop (distal ileum, cecum) rapidly "slid" into the right lower abdomen. The seemingly random position of the tertiary small-intestinal loops may have a biomechanical origin. CONCLUSIONS: The interpretation of "intestinal rotation" as a mechanistic rather than a descriptive concept underlies much of the confusion accompanying the physiological herniation. We argue, instead, that the concept of "en-bloc rotation" of the developing midgut is a fallacy of schematic drawings. Primary, secondary and tertiary loops arise in a hierarchical fashion. The predictable position and growth of secondary loops is pre-patterned and determines adult intestinal topography. We hypothesize based on published accounts that malrotations result from stunted development of secondary loops.

PMID 26297675

Intestinal Rotation and Physiological Umbilical Herniation During the Embryonic Period

Anat Rec (Hoboken). 2016 Feb;299(2):197-206. doi: 10.1002/ar.23296. Epub 2015 Dec 18.

Ueda Y1, Yamada S1,2, Uwabe C2, Kose K3, Takakuwa T1.


Drastic changes occur during the formation of the intestinal loop (IL), including elongation, physiological umbilical herniation (PUH), and midgut rotation. Fifty-four sets of magnetic resonance images of embryos between Carnegie stage (CS) 14 and CS 23 were used to reconstruct embryonic digestive tract in three dimensions in the Amira program. Elongation, PUH, and rotation were quantified in relation to the proximal part of the superior mesenteric artery (SMA), designated as the origin. Up to CS 16, IL rotation was initially observed as a slight deviation of the duodenum and colorectum from the median plane. The PUH was noticeable after CS 17. At CS 18, the IL showed a hairpin-like structure, with the SMA running parallel to the straight part and the cecum located to the left. After CS 19, the IL began to form a complex structure as a result of the rapid growth of the small intestinal portion. By CS 20, the IL starting point had moved from the right cranial region to an area caudal to the origin, though elongation of the duodenum was not conspicuous-this was a change of almost 180° in position. The end of the IL remained in roughly the same place, to the left of and caudal to the origin. Notably, the IL rotated around the origin only during earlier stages and gradually moved away, running transversely after CS 19. The movements of the IL may be explained as the result of differential growth, suggesting that IL rotation is passive. Anat Rec, 299:197-206, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc. KEYWORDS: human embryo; intestinal development; magnetic resonance imaging; midgut rotation; three-dimensional reconstruction

PMID 26599074


How to make an intestine

Development. 2014 Feb;141(4):752-60. doi: 10.1242/dev.097386.

Wells JM1, Spence JR.


With the high prevalence of gastrointestinal disorders, there is great interest in establishing in vitro models of human intestinal disease and in developing drug-screening platforms that more accurately represent the complex physiology of the intestine. We will review how recent advances in developmental and stem cell biology have made it possible to generate complex, three-dimensional, human intestinal tissues in vitro through directed differentiation of human pluripotent stem cells. These are currently being used to study human development, genetic forms of disease, intestinal pathogens, metabolic disease and cancer. KEYWORDS: Directed differentiation; Embryonic stem cells; Gastrointestinal disease; Gut tube; Intestinal morphogenesis; Pluripotent stem cells

PMID 24496613


Development of the human tail bud and splanchnic mesenchyme

Congenit Anom (Kyoto). 2013 Mar;53(1):27-33. doi: 10.1111/j.1741-4520.2012.00387.x.

Hashimoto R1.

Abstract The purpose of this paper was to shed some light on anorectal development from a viewpoint of the tail bud and splanchnic mesenchyme for better understanding of the morphogenesis of the human anorectum. Human embryos ranging from Carnegie stage 11 to 23 (CS 11 to 23) were adopted in this study. Seventeen embryos preserved at the Congenital Anomaly Research Center of Kyoto University Graduate School of Medicine were histologically examined. The cloaca, extending caudally to the hindgut, was dramatically enlarged, particularly both its dorsal portion and membrane, that is, the cloacal membrane resulting from the development of the tailgut derived from the tail bud. The splanchnic mesenchyme surrounding the hindgut was spread out in the direction of the urorectal septum ventrally, suggesting that it participated in the formation of the septum. No fusion of the urorectal septum and the cloacal membrane was found. The splanchnic mesenchyme proliferated and developed into smooth muscle (circular and longitudinal) layers from cranial to caudal along the hindgut. The tail bud seems to cause both the adequate dilation of the dorsal cloaca and the elongation of the cloacal membrane; its dorsal portion in particular will be necessary for normal anorectal development. The splanchnic mesenchyme developed and descended toward the pectinate line and formed the internal sphincter muscle at the terminal bowel. © 2012 The Author. Congenital Anomalies © 2012 Japanese Teratology Society.

PMID 23480355

Early Structured Surgical Management Plan for Neonates with Short Bowel Syndrome May Improve Outcomes

World J Surg. 2013 Mar 29. [Epub ahead of print]

Wood SJ, Khalil B, Fusaro F, Folaranmi SE, Sparks SA, Morabito A. Source Royal Manchester Children's Hospital, University of Manchester, Oxford Road, Manchester, M13 9WL, UK, Abstract BACKGROUND: In children with short bowel syndrome, maximal adaptation of the bowel after extensive resection is thought to occur during the first 2 years of life. The aim of the present study was to review children with short bowel syndrome from two intestinal rehabilitation centers, comparing those undergoing lengthening procedures <365 days of age (early) versus those whose lengthening procedure was carried out >365 days of age (late). METHODS: Retrospective data collection was performed from January 2004 to December 2010 in Manchester, UK, and from December 2006 to December 2010 in Brussels, Belgium. Both medical centers follow a similar intestinal rehabilitation program (IRP). Data collected included population demographics, bowel length preoperatively and postoperatively, age at operation, parenteral nutrition (PN), central access, and complications. RESULTS: Complete data were available for eight children who underwent lengthening surgery at <365 days of age, and six who underwent the procedure at >365 days of age. Diagnoses were similar. Groups were matched for gestation and birthweight, with no statistical difference in preoperative and postoperative bowel lengths. The mean duration of PN postoperatively was 378 days in the early cohort and 589 days in the late cohort. This trended toward statistical significance (p = 0.071). Full enteral autonomy was achieved at 17 months (early) and 59 months (late) (p = 0.01). Patients in the early group required fewer central lines than those operated on later (p = 0.035). CONCLUSIONS: Enrolling children into an IRP involving early (<365 days of age) lengthening surgery allows a shorter postoperative time to allow weaning to full enteral nutrition, as well as fewer central lines. Both outcomes provide benefits for the child and family, allowing an earlier return to normal life.

PMID 23539194


Bmp7 functions via a polarity mechanism to promote cloacal septation

PLoS One. 2012;7(1):e29372. Epub 2012 Jan 13.

Xu K, Wu X, Shapiro E, Huang H, Zhang L, Hickling D, Deng Y, Lee P, Li J, Lepor H, Grishina I. Source Department of Urology, School of Medicine, New York University, New York, New York, United States of America. Abstract BACKGROUND: During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse. CONCLUSION/SIGNIFICANCE: Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations.

PMID 22253716


Intestinal development and differentiation

Exp Cell Res. 2011 Nov 15;317(19):2702-10. Epub 2011 Sep 24.

Noah TK, Donahue B, Shroyer NF. Source Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.


In this review, we present an overview of intestinal development and cellular differentiation of the intestinal epithelium. The review is separated into two sections: Section one summarizes organogenesis of the small and large intestines, including endoderm and gut tube formation in early embryogenesis, villus morphogenesis, and crypt formation. Section two reviews cell fate specification and differentiation of each cell type within the intestinal epithelium. Growth factor and transcriptional networks that regulate these developmental processes are summarized.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 21978911

Embryology of the midgut

Semin Pediatr Surg. 2011 Aug;20(3):145-51. doi: 10.1053/j.sempedsurg.2011.03.005.

Metzger R1, Metzger U, Fiegel HC, Kluth D. Author information


In most textbooks of embryology and pediatric surgery, the puzzling spectrum of midgut "malrotations" is explained by an "impaired" process of rotation of the midgut. However, this "process of rotation" is explained in a rather schematic way and aims more to explain pathologic findings whereas detailed embryologic investigations are still rare in this field. Good animal models which would allow the comparison of normal and abnormal midgut development are missing. In this paper we describe the development of the midgut in form of an atlas. Scanning electron microscopy is used in rat embryos to illustrate the crucial embryologic processes of midgut development. The main result shown in these illustrations is that clear signs of a process of rotation are missing. Copyright © 2011 Elsevier Inc. All rights reserved.

PMID 21708334


J Cell Mol Med. 2011 Feb 25. doi: 10.1111/j.1582-4934.2011.01287.x. [Epub ahead of print]

Radenkovic G. Source Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia.


At the end of the embryonic period of human development, c-kit immunoreactive (c-kit IR) cells identifiable as interstitial cells of Cajal (ICC) are present in the oesophagus and stomach wall. In the small and large bowel, c-kit-IR cells appear later (in the small bowel at 9 weeks, and in the colon at 10-12 weeks), also in the MP region. The object of the present study was to determine the timing of appearance and distribution of c-kit IR cells in the human embryonic and fetal duodenum. I used immunohistochemistry to examine the embryonic and fetal duodenum for cells expressing CD117 (Kit), expressed by mature ICC and ICC progenitor cells and CD34 to identify presumed ICC progenitors. Enteric plexuses were examined by way of anti-neuron specific enolase and the differentiation of smooth muscle cells was studied using anti-desmin antibodies. At the end of the embryonic period of development, c-kit IR cells were solely present in the proximal duodenum in the form of a wide belt of densely packed cells around the inception of the MP ganglia. In the distal duodenum, c-kit IR cells emerged at the beginning of the fetal period in the form of thin rows of pleomorphic cells at the level of the MP. From the beginning of the 4(th) month, the differences in the distribution of ICC in the different portions of the duodenum were established, and this relationship was still present in later developmental stages. In fact, in the proximal duodenum, ICC of the myenteric plexus (ICC-MP), ICC of the circular muscle (ICC-CM), and ICC of the septa (ICC-SEP) were present, and in the distal duodenum ICC-MP and ICC-SEP only. In conclusion, in the humans there is a difference in the timing and patterns of development of ICC in the proximal duodenum compared to the distal duodenum.


PMID: 21352475

Spatiotemporal expression of Wnt5a during the development of the hindgut and anorectum in human embryos

Int J Colorectal Dis. 2011 Aug;26(8):983-8. doi: 10.1007/s00384-011-1191-y. Epub 2011 Mar 24.

Li FF1, Zhang T, Bai YZ, Yuan ZW, Wang WL.


PURPOSE: The aim of the study was to determine the spatiotemporal expression of Wnt5a during hindgut and anorectum development in human embryos and to explore the possible role of Wnt5a during the morphogenesis of the human hindgut and anorectum. MATERIALS AND METHODS: The embryos (n = 107) were sectioned serially and sagittally, using Wnt5a immunohistochemical staining on the caudal midline from the 4th-9th weeks of gestation. RESULTS: From the 4th-7th week of gestation, the Wnt5a-positive cells were mainly located on the epithelium of the apical urorectal septum, hindgut, and cloacal membrane. After the anorectum and the urogenital sinus (UGS) opened to the amniotic cavity during the 7th week, the Wnt5a-positive cells disappeared and remained negative up to the 9th week on the epithelium of the anal canal. CONCLUSIONS: The expression of Wnt5a was constantly active during human hindgut and anorectum development and disappeared after the anus formed, suggesting that Wnt5a plays an important role in human hindgut and anorectal morphogenesis. PMID 21431850


Fgf9 signaling regulates small intestinal elongation and mesenchymal development

Development. 2008 Sep;135(17):2959-68. Epub 2008 Jul 24.

Geske MJ, Zhang X, Patel KK, Ornitz DM, Stappenbeck TS. Source Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.


Short bowel syndrome is an acquired condition in which the length of the small intestine is insufficient to perform its normal absorptive function. Current therapies are limited as the developmental mechanisms that normally regulate elongation of the small intestine are poorly understood. Here, we identify Fgf9 as an important epithelial-to-mesenchymal signal required for proper small intestinal morphogenesis. Mouse embryos that lack either Fgf9 or the mesenchymal receptors for Fgf9 contained a disproportionately shortened small intestine, decreased mesenchymal proliferation, premature differentiation of fibroblasts into myofibroblasts and significantly elevated Tgfbeta signaling. These findings suggest that Fgf9 normally functions to repress Tgfbeta signaling in these cells. In vivo, a small subset of mesenchymal cells expressed phospho-Erk and the secreted Tgfbeta inhibitors Fst and Fstl1 in an Fgf9-dependent fashion. The p-Erk/Fst/Fstl1-expressing cells were most consistent with intestinal mesenchymal stem cells (iMSCs). We found that isolated iMSCs expressed p-Erk, Fst and Fstl1, and could repress the differentiation of intestinal myofibroblasts in co-culture. These data suggest a model in which epithelial-derived Fgf9 stimulates iMSCs that in turn regulate underlying mesenchymal fibroblast proliferation and differentiation at least in part through inhibition of Tgfbeta signaling in the mesenchyme. Taken together, the interaction of FGF and TGFbeta signaling pathways in the intestinal mesenchyme could represent novel targets for future short bowel syndrome therapies.

PMID: 18653563


Development of the vermiform appendix during the fetal period

Surg Radiol Anat. 2004 Jun;26(3):202-7. Epub 2004 Apr 9.

Malas MA1, Sulak O, Gökçimen A, Sari A.


This study aimed to determine the location and development of the vermiform appendix (VA) in terms of morphometry. It was carried out on 80 human fetuses that exhibited neither external pathology nor anomaly and whose gestational ages were between 10 and 40 weeks. The location of the VA and cecum was established. Total VA diameter, lumen diameter, wall thickness, serosa, muscularis and mucosa thickness were measured on microscope slides. The VA was almost always observed in the subcecal region during the fetal period. The length of the VA and the attachment length of the meso-appendix to the VA increased with the gestational age. Lymphocyte aggregation was first seen at the 17th week of the fetal period. Positive and meaningful correlation was found between gestational age and morphometric parameters of the VA. A significant difference was found between the genders in the thickness of mucosa, which was larger in girls (p<0.05). When the proximal, median and distal parts were compared, the thickness of serosa between the proximal and distal parts was also significantly different (p<0.05). The present study has revealed that the VA matures in the second trimester during the fetal period. Furthermore, the morphologic development of the VA is almost uniform from the proximal to distal part.

PMID 15173960 DOI: 10.1007/s00276-003-0208-9

The development of large intestine during the fetal period

Early Hum Dev. 2004 Jun;78(1):1-13.

Malas MA, Aslankoç R, Ungör B, Sulak O, Candir O. Source Department of Anatomy, Medical Faculty, Suleyman Demirel University, Tip Fakültesi, Anatomi Anabilim Dali, 32260 Isparta, Turkey.


OBJECTIVE: The aim of this study is to determine the colon types, developmental change of the colon morphology during the fetal period. METHODS: The study was realised on 131 human fetuses (male 69, female 62) ages between 10 and 40 weeks, which have no external pathology and anomalies. The colon types were evaluated in two parts. As the first part, the colon part between the ileal orifice and sigmoid colon was typed. The sigmoid colon was typed as the second part. The macroscopic diameters of parts of the colon and the thicknesses of wall layers of ascending and descending colons were measured under the light microscope. RESULTS: For the proximal part of the colon, there were seven types of colon, and there were five types for the sigmoid colon. For the first part, transverse type colon was a rare type during the fetal period (3%). The oblique type colon was observed mostly in the first and second trimester during the fetal period. Adult type colon was the most common type in the third trimester and full-term groups. The pendulous type colon was observed mostly in the third trimester. The development of the haustra and tenia coli in the first trimester was quite slow, but later the development increased more and more, and during the full-term period, the haustra and tenia coli could be seen clearly. CONCLUSION: The percentage distribution of the colon types between the trimesters was significant. It was observed that the maturation of haustra and tenia coli started from the ascending colon and progressed towards the sigmoid colon. The thickness of the tunica mucosa layer both in the ascending and in descending colon part increased considerably in the middle of the second trimester.

PMID 15177668

Development of the vermiform appendix during the fetal period

Surg Radiol Anat. 2004 Jun;26(3):202-7. Epub 2004 Apr 9.

Malas MA, Sulak O, Gökçimen A, Sari A. Source Department of Anatomy, Medical Faculty, Süleyman Demirel University, Isparta, Turkey.


This study aimed to determine the location and development of the vermiform appendix (VA) in terms of morphometry. It was carried out on 80 human fetuses that exhibited neither external pathology nor anomaly and whose gestational ages were between 10 and 40 weeks. The location of the VA and cecum was established. Total VA diameter, lumen diameter, wall thickness, serosa, muscularis and mucosa thickness were measured on microscope slides. The VA was almost always observed in the subcecal region during the fetal period. The length of the VA and the attachment length of the meso-appendix to the VA increased with the gestational age. Lymphocyte aggregation was first seen at the 17th week of the fetal period. Positive and meaningful correlation was found between gestational age and morphometric parameters of the VA. A significant difference was found between the genders in the thickness of mucosa, which was larger in girls (p<0.05). When the proximal, median and distal parts were compared, the thickness of serosa between the proximal and distal parts was also significantly different (p<0.05). The present study has revealed that the VA matures in the second trimester during the fetal period. Furthermore, the morphologic development of the VA is almost uniform from the proximal to distal part.

PMID 15173960


Timetable for intestinal rotation in staged human embryos and fetuses

Birth Defects Res A Clin Mol Teratol. 2003 Nov;67(11):941-5.

Kim WK, Kim H, Ahn DH, Kim MH, Park HW.

Department of Anatomy, College of Medicine, Hanyang University, Seoul, South Korea. Abstract BACKGROUND: The existing data on intestinal rotation during human development are contradictory regarding the timing of major events, and as such an exact timetable for rotation of the intestine in humans is not yet available.

METHODS: We studied the initial formation and rotation of the intestine by microdissection and histological observations in 72 human embryos and fetuses at two to 12 weeks postfertilization. The embryos were classified according to the Carnegie staging system.

RESULTS: The primordium of the primitive gut was first observed as a yolk sac at stage 5. With the formation of the embryonic foldings, three divisions of the primitive gut (the foregut, midgut, and hindgut) were observed at stage 10. At stage 12, the primitive gut was located on the midline. At stage 15, a 90 degrees counterclockwise rotation of the intestine began. At stage 16, herniation of the intestine into the umbilical cord was not evident in observations of the external form or a transversely sectioned embryo, but was evident in a sagittally sectioned embryo. There was another 90 degrees counterclockwise rotation at stage 20. Reduction of the intestine was a rapid process, since it was still in the cord in fetuses of <40 mm crown-rump length (CRL), and was reduced above 40 mm in general during nine weeks of development. When the intestine returned to the abdominal cavity, the cecum was located in the right lower quadrant (the adult position).

CONCLUSIONS: We have developed a standard timetable to describe the rotation of the intestine. The current results will be helpful in studies describing the pathogenesis of some developmental abnormalities in the intestine due to abnormal rotation.

Copyright 2003 Wiley-Liss, Inc. PMID 14745932

The development of jejunum and ileum during the fetal period

Early Hum Dev. 2003 Nov;74(2):109-24.

Malas MA, Aslankoç R, Ungör B, Sulak O, Candir O. Source Department of Anatomy, Medical Faculty, Suleyman Demirel University, 32260-Isparta, Turkey.


OBJECTIVE: In our study, the morphologic structures of the jejunum and ileum sections of small intestine were investigated in human fetuses during the fetal period. MATERIALS AND METHODS: The study was realised on 131 human fetuses (male: 69; female: 62) with ages between 10 and 40 weeks, which have got no external pathology and anomalies. The external sizes of fetuses were measured, and then the structures in the abdominal cavity were determined by the abdominal dissection. The localization of jejunum and ileum, duodenojejunal flexure and ileal orifice points, the measurements of macroscopic diameters, types of the mass of jejunum and ileum and the localization according to the abdominal regions of the mass of jejunum and ileum were determined. Also, the samples of the jejunum and ileum were examined both macroscopically and microscopically. The thickness of tunica serosa, tunica muscularis and tunica mucosa was determined under the light microscope. RESULTS: According to the sexes, gestational ages and groups, the averages and the standard deviations of the all parameters were determined. The correlations between the parameters were determined. The percentage of parameters was compared according to sex and among groups. No differences were found in parameters between sexes (p<0.05). The macroscopic parameters were increased according to the gestational age. The thickness of tunica serosa did not change according to the gestational age. CONCLUSION: It is thought that the data we have will help the evaluation of jejunum and ileum in intrauterine period; we also believe that the data in our study may help in the diagnosis and treatment of anomalies and pathologies in fetal period that belongs to jejunum and ileum. PMID 14580751


The ontogeny of the small intestinal epithelium

JPEN J Parenter Enteral Nutr. 1999 Sep-Oct;23(5 Suppl):S3-6.

Lebenthal A1, Lebenthal E. Author information


The primary factors in feeding premature infants are dependent on the development and maturation of digestion and absorption. The maturation of digestive and absorptive functions of carbohydrates, proteins, fats, minerals, and vitamins in the young premature infant were determined in relation to availability of hydrolytic enzymes, such as lipases, proteases, amylases, glucosidases, and lactase. The feeding is dependent on the ability of the premature infant to secrete salivary enzymes, gastric acid, pepsin, pancreatic exocrine enzymes, the presence of enterohepatic circulation, and the hydrolytic and absorptive capacity of the entercocyte. To evaluate the complexity of the gut maturation process, we proposed a unified concept where the ontogeny of the gastrointestinal system is the result of the following four major determinants: genetic endowment, intrinsic developmental and biological clock, endogenous regulatory mechanisms, and environmental influences. The developmental clock represents a predetermined temporal sequence of happenings in ontogeny that is inherently controlled. By 20 weeks of gestation, the anatomic differentiation of the fetal gut has progressed to the extent that it resembles that of a newborn. Secretory and absorptive functions, however, develop at different rates; the intestinal absorptive process is only partially available before 26 weeks of gestation, whereas gastric and pancreatic secretion is only basal and can be stimulated only partially even in the full-term newborn period. Regulatory mechanisms control the expression of the genetic endowment at various stages in gastrointestinal development. Neural-hormonal factors play major roles in the ontogeny of the gut. Adrenalectomy, hypophysectomy, and thyroidectomy delay the development of the gut. Administration of glucocorticoids or thyroxine at the critical stage in maturation causes early appearance of enzymes within the intestine. Other hormones that are potentially important in regulating gastrointestinal development include cholecystokinin, gastrin, secretin, which have trophic effects on the gastrointestinal tract, and insulin, insulin-like growth factors, and epidermial growth factor. The development of gastrointestinal secretory function, particularly in response to hormonal stimulation, has received considerable attention. The degree of response of the target cell is determined not only by the amount of effective hormone reaching it but also by the number and affinity of receptors on its surface. Human newborns have high levels of gastrin in their sera, yet have low acid output. Exogenous gastrin is an ineffective stimulant despite the presence of seemingly "anatomically developed" parietal cells. It seems that neither endogenous nor exogenous gastrin has an effect on the target cell. If one accepts the role of circulating gastrin levels in the regulation of its own receptor, one can hypothesize the absence of a regulatory effect of gastrin in the newborn period. It was shown that hormonal regulation of migrating activity by motilin is also absent in the preterm and term infant. Plasma levels of motilin in neonates are comparable to those found in adults, but migrating motor complexes occur in the absence of cycling of plasma concentrations. Interestingly, however, the motilin receptor appears to be present. In conclusion, the feeding mode content, concentration, and volume of the very young premature infant can be assessed by the development of digestive and absorptive capacity and gut motility. The concomitant changes in gut hormones and regulatory peptides during ontogeny and feeding will add a new dimension in the understanding of when, what, and how to feed the very young premature infant.

PMID 10483884


Small intestinal length: a factor essential for gut adaptation

Gut. 1991 Nov;32(11):1321-3.

Weaver LT, Austin S, Cole TJ. Source MRC Dunn Nutrition Unit, Cambridge.


Changes in small intestinal structure, cytokinetics, and function are dynamic ways in which the gut adapts to diet, disease, and damage. Adequate length provides a static 'reserve' permitting an immediate response to pathophysiological changes. The length of the small intestine from conception to adulthood using data taken from eight published reports of necropsy measurement of 1010 guts is described. Mean length at 20 weeks' gestation was 125 cm, at 30 weeks' 200 cm, at term 275 cm, at 1 year 380 cm, at 5 years 450 cm, at 10 years 500 cm, and at 20 years 575 cm. Prenatal small intestinal growth exceeded that of body length according to the law: small intestinal length alpha body length to the power 4/3. After birth there was a noticeable deceleration: small intestinal length alpha body length to the power 1/2. The coefficient of variation of small intestinal length postnatally was 24%, sixfold greater than for body length. The rapid prenatal small intestinal growth rate ensures that the mature newborn has adequate small intestine to meet postnatal nutritional demands, but handicaps the preterm infant who undergoes intestinal resection. The wide variation in lengths suggests a 'surplus' surface area that is immediately available to respond, independent of dynamic mucosal changes, to fluctuations in food availability, local intestinal disease, damage, rapid transit, and resection.

PMID: 1752463

Postulated functional regions

Duodenum - principal site for iron absorption. Ileocecal valve - only site in the gastrointestinal tract for Vitamin B12 and bile acid absorption?

  1. Wang S, Cebrian C, Schnell S & Gumucio DL. (2018). Radial WNT5A-Guided Post-mitotic Filopodial Pathfinding Is Critical for Midgut Tube Elongation. Dev. Cell , 46, 173-188.e3. PMID: 30016620 DOI.