05.28.09(a): development of the gastrointestinal system

Author(s): Matthew Velkey, 2009

License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution – Non-Commercial – Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/

We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material.

Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content.

For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.

Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition.

Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

Citation Keyfor more information see: http://open.umich.edu/wiki/CitationPolicy

Use + Share + Adapt

Make Your Own Assessment

Creative Commons – Attribution License

Creative Commons – Attribution Share Alike License

Creative Commons – Attribution Noncommercial License

Creative Commons – Attribution Noncommercial Share Alike License

GNU – Free Documentation License

Creative Commons – Zero Waiver

Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ

Public Domain – Expired: Works that are no longer protected due to an expired copyright term.

Public Domain – Government: Works that are produced by the U.S. Government. (USC 17 § 105)

Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain.

Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ

Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair.

To use this content you should do your own independent analysis to determine whether or not your use will be Fair.

{ Content the copyright holder, author, or law permits you to use, share and adapt. }

{ Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. }

{ Content Open.Michigan has used under a Fair Use determination. }

Development of the Gastrointestinal System

Matt Velkey

Spring 2009

General outline/learning objectives:

• Formation of the gut tube - morphogenic events• Cranial/caudal patterning of the gut tube• Radial patterning of the gut tube• *Regional patterning: Formation of intestinal villi*• Organogenesis: Inductive events in formation of

gut-associated organs (liver, pancreas)

Suggested reading: Sadler, Chapter 14

Major themes:Regional patterning and cell movements set the stage for a series of inductive events that form organs:

• Importance of cell-cell communication• Competency and/or signals may be regionally

and/or temporally limited.

Factors that control proliferation/differentiationduring organogenesis may be later associatedwith carcinogenesis (Sonic Hedgehog, Shh)

There are distinct stages in organ formation:• Specification• Anlage (bud) formation • Proliferation• Differentiation

Vocabulary:• Competency: The ability of a cell or group of cells to

respond to a particular signal• Endoderm: layer of post-gastrulation embryo that gives rise

to the epithelium of the gut tube and gut-derived organs

• Mesoderm/Mesenchyme: layer of post-gastrulation embryo that gives rise to the surrounding tissue of the gut tube

• Cell-cell communication: Passage of signals between two groups of cells (usually endoderm and mesoderm); these signals are crucial in the specification of cell fate and proliferation/differentiation decisions

• Sonic Hedgehog (Shh): secreted signaling molecule made by the endoderm; important in organ-specific development

• BMPs, FGFs: Secreted signaling molecules important in liver and pancreas specification

Gastrulation:

Epiblast cells migrate through the primitive streak.

Definitive (embryonic) endoderm cells displace the hypoblast.

Mesoderm spreads between endodermand ectoderm.

Langman’s Medical Embryology, 9th ed. 2004.

Early mesodermal patterning:

(buccopharyngeal membrane)

Specific regions of the epiblast migrate through the streak at different levelsand assume different positions withinthe embryo:

Cranial to caudal:Notochord (n)Paraxial mesoderm (pm)Intermediate mesoderm (im)*Lateral plate mesoderm (lpm)Extraembryonic mesoderm (eem)

Source Undetermined

The developing endoderm (yellow) is initially open to the yolk sac (the cardiac region is initially most anterior)…

Longitudinal folding at both ends of the embryo andlateral folding at the sides of the embryobring the endoderm inside and form the gut tube.

Endoderm


Folding creates the anterior and posterior intestinal portals(foregut and hindgut, respectively)

The cardiac region is brought to the ventral side of thedeveloping gut tube.

Cloacal membrane

Juxtaposition of ectoderm and endoderm at:Oropharyngeal (buccopharyngeal) membrane - future mouthCloacal membrane - future anus


Gut-associated organs begin to form as buds from the endoderm: (e.g., thyroid, lung, liver, pancreas)

Midgut opening to the yolk sac progressively narrows


By the end of the first month:The stomach bulge is visible, Dorsal pancreas has begun to bud

Connection of the midgut to the yolk sac is reduced toa yolk stalk


With lateral folding, mesoderm is

recruited to gut wall

• Lateral folding of the embryo completes the gut tube

• Mesodermal layer of the gut tube is called splanchnic (visceral) mesoderm - derived from lateral plate mesoderm

• Somatic mesoderm lines body cavity



Foregut: pharynx thyroidesophagus parathyroid glandsstomach tympanic cavityproximal duodenum trachea, bronchi, lungs

liver, gallbladderpancreas

Midgut: proximal duodenum toright half oftransversecolon

Hindgut: left half of urinary bladdertransversecolon to anus

Gut tube proper Derivatives of gut tube

(These three regions are defined by their blood supply)

25 days 32 days

Celiac artery supplies the foregutSuperior mesenteric artery supplies the midgutInferior mesenteric artery supplies the hindgut


Gut = bilayered tube (endoderm surrounded by mesoderm)

Regional gut tube patterning and organogenesis requirebi-directional endoderm-mesoderm cross-talkand inductive signals from other nearby structures

Regional patterning of the gut tube

Source Undetermined

Regional patterning of the gut tube - the Hox codeHox genes are evolutionarily conserved transcription factors that are used in regional patterning (flies to mammals).

The gut has an cranial-caudal Hox gene expression pattern (code) similar to that seen in neural tissue.

Some Hox genes are expressed in mesoderm, in overlapping patterns; some are expressed in endoderm.

Hox gene expression boundaries correspond to morphologically recognizable elements in the GI tract.

Hox gene expression is important for formation of major sphincters (red circles)

Regulatory networks in time and space: • Regional variation in regulatory pathways due to:• Regional variation in competence (induction of mesodermal Hoxd-13 by Shh)• Temporal variation in signaling (restriction of BMP from stomach mesoderm)

How is the patterning established? How does it play out in regional organogenesis?The role of Sonic hedgehog (Shh) in gut patterning….

Hedgehog signaling is important for concentric (radial) patterning of the entire gut tube

Hh

Fetus

High Hedgehog concentration inhibits muscle formation;

Sm. Musc.Sm. Musc.Sm. MuscSm. Musc

Low Hedgehog concentration stimulates muscle differentiation

Morphogen: induces different cell fates at different concentrationsof signal

Adult Esophagus

Source Undetermined

Wheater’s Functional Histology

M. Velkey.

Esophageal/Gastric border

Esophagus Stomach

Cranial-caudal pattern of the gut tube is played out as regional organ differentiation.

Distinct borders form.

Source Undetermined

Pyloric border (gastric/duodenal)

Stomach Duod.

Stomach Duodenum

Source Undetermined Source Undetermined

Regional Organogenesis: Esophagus

• Region of foregut just caudal to lung bud develops into esophagus –errors in forming the esophagotracheal septa and/or re-canalization lead to tracheoesophageal fistulas and/or esophageal atresia, respectively.

• Endodermal lining is stratified columnar and proliferates such that the lumen is obliterated; patency of the lumen established by re-canalization –errors in this process lead to esophageal stenosis

– NOTE: this process of recanalization occurs throughout the gut tube, so occlusion can occur anywhere along the GI tract (e.g. duodenal stenosis)

• Tube initially short and must grow in length to “keep up” with descent of heart and lungs –failure of growth in length leads to congenital hiatal hernia in which the cranial portion of the stomach is pulled into the hiatus.


Regional Organogenesis: Stomach

• Stomach appears first as a fusiform dilation of the foregut endoderm which undergoes a 90° rotation such that the left side moves ventrally and the right side moves dorsally (the vagus nerves follow this rotation which is how the left vagus becomes anterior and the right becomes posterior).

• Differential growth occurs to establish the greater and lesser curvatures• Unlike other parts of the gut tube, the dorsal AND ventral mesenteries are retained to become the greater and lesser

omenta, respectively• Caudal end of the stomach separated from the duodenum by formation of the pyloric sphincter (dependent on factors

such as SOX-9, NKX-2.5, and BMP-4 signaling) –errors in this process lead to pyloric stenosis.

Greater omentum


Pyloric Stenosis• Rather common malformation: present in

0.5% - 0.1% of infants

• Characterized by very forceful (aka “projectile”), non-bilious vomiting ~1hr. after feeding (when pyloric emptying would occur).

NOTE: the presence of bile would indicate POST-duodenal blockage of some sort.

• Hypertrophied sphincter can often be palpated as a spherical nodule; peristalsis of the sphincter seen/felt under the skin.

• Stenosis is due to overproliferation / hypertrophy of pyloric sphincter… NOT an error in re-canalization.

• More common in males than females, so most likely has a genetic basis which is as yet undetermined.

University of California, San Francisco.

Regional Organogenesis: Liver & Pancreas

• Liver and pancreas arise from foregut endoderm in response to signals from nearby mesoderm

• Pancreas actually has ventral and dorsal components, each specified in a different manner


Cardiac mesoderm and septum transversum specifies liver

• FGFs secreted by cardiac mesoderm and BMPs secreted by septum transversum induce liver from foregut endoderm

• Endoderm just caudal to liver bud is out of reach from these signals and develops into pancreas

ventral pancreas


Once specified, the hepatoblasts proliferate and invadethe septum transversum

Angioblasts (endothelial cell precursors) are found next to thethickening pre-hepatic endoderm before invasion of the liver bud;

these endothelial cells supply critical growth signals

Three signals for liver formation:FGF from cardiac mesenchyme; BMPs from septum transversum

mesenchyme, VEGF from endothelial cells

(anlage formation)

Source Undetermined

The dorsal pancreas is specified by signaling from the notochord

Signaling from the notochord represses Shh in foregut endoderm, which permits pancreatic differentiation.

Rotation of the duodenum brings the ventral and dorsal pancreas together

Aberrations in this process may result in an annular pancreas, which can constrict the duodenum

Image of ventral and

dorsal pancreas removed.

Original Image: Shoenwolf, et al. Larsen’s Human Embryology, 4th Edition.

Development of the midgut and colonHerniation and rotation:

– Growth of the GI tract exceeds volume of abdominal cavity so the tube herniates through umbilicus

– While herniated, gut undergoes a primary rotation of 90° “counterclockwise” (when looking at the embryo); this corresponds with the rotation of the stomach, and positions the appendix on the left.

– With the growth of the embryo, the abdominal cavity expands thus drawing the gut tube back within the abdominal cavity and causing an additional, secondary rotation of 180° CCW (positioning the appendix on the RIGHT)

– Once in the abdominal cavity, the colon continues to grow in length, pushing the appendix to its final position in the lower right quadrant.

Image of development of

midgut and colon removed.

Original Image: Larsen’s Human Embryology, 4th Edition.

Defects associated with gut herniation and rotation: oomphaocoele


Defects associated with gut herniation and rotation: vitelline duct abnormalities


Defects associated with gut herniation and rotation: abnormal rotation

Absent or incomplete secondary rotation

Reversed primary rotation (90° CW)


Defects associated with gut herniation and rotation: volvulus

Fixation of a portion of the gut tube to the body wall; subsequent rotation causes twisting of the tube, possibly resulting in stenosis and/or ischemia.

Image of defects with gut herniation and

rotation removed.

Original Image: Carlson - Human Embryology and Developmental Biology, 4th Edition.

Development of the hindgut

• Derivatives of the hindgut include everything caudal to the distal 1/3 of the transverse colon.

• Distalmost portion (sigmoid colon and rectum) divides cloaca into the anorectal canal and urogenitial canals –errors in this process can lead to imperforate anus (“A” on right), atresia (B), and/or fistulas (C – F)

• As with the rest of the GI tract, enteric neurons arise from vagal neural crest. Distalmost portions of the hindgut are farthest away and therefore more sensitive to perturbations in migration (e.g. mutations in RET), resulting in congenital megacolon (Hirschspring’s Disease).

anal atresiaimperforate anus

anoperineal fistula rectovaginal fistula

rectourethral fistula rectovesical fistula


Langman’s Medical Embryology, 9th ed. 2004.Slide 8: Source UndeterminedSlide 9: Langman’s Medical Embryology, 9th ed. 2004.Slide 10: Langman’s Medical Embryology, 9th ed. 2004.Slide 11: Langman’s Medical Embryology, 9th ed. 2004.Slide 12: Langman’s Medical Embryology, 9th ed. 2004.Slide 13: Langman’s Medical Embryology, 9th ed. 2004.; Langman’s Medical Embryology, 9th ed. 2004.Slide 15: Langman’s Medical Embryology, 9th ed. 2004.Slide 16: Source UndeterminedSlide 17: Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. Slide 18: Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 19: Source Undetermined; M. Velkey; Wheater’s Functional Histology Slide 20: Source UndeterminedSlide 21: Source Undetermined; Source UndeterminedSlide 22: Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc.;

Langman’s Medical Embryology, 9th ed. 2004. Slide 23: Langman’s Medical Embryology, 9th ed. 2004.Slide 24: University of California, San Francisco. Slide 25: Langman’s Medical Embryology, 10th ed. 2006.Slide 26: Langman’s Medical Embryology, 10th ed. 2006.Slide 27: Source UndeterminedSlide 28: Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 29: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of

Elsevier, Inc. Slide 30: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4th Edition. Copyright 2008 Churchill Livingston, an imprint of

Elsevier, Inc. Slide 31: Langman’s Medical Embryology, 9th ed. 2004.Slide 32: Langman’s Medical Embryology, 9th ed. 2004.Slide 33: Langman’s Medical Embryology, 10th ed. 2006.Slide 34: Original Image Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of

Elsevier, Inc. Slide 35: Carlson: Human Embryology and Developemental Biology, 4th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc.;


Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy

05.28.09(a): development of the gastrointestinal system

Education