Authors Matthew Velkey 2009 License Unless otherwise noted

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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. There are distinct stages in organ formation: • Specification • Anlage (bud) formation • Proliferation • Differentiation Factors that control proliferation/differentiation during organogenesis may be later associated with carcinogenesis (Sonic Hedgehog, Shh)

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 endoderm and ectoderm. Langman’s Medical Embryology, 9 th ed. 2004.

Early mesodermal patterning: (buccopharyngeal membrane) Specific regions of the epiblast migrate through the streak at different levels and assume different positions within the embryo: Cranial to caudal: Notochord (n) Paraxial mesoderm (pm) Intermediate mesoderm (im) *Lateral plate mesoderm (lpm) Extraembryonic mesoderm (eem) Source Undetermined

Endoderm Langman’s Medical Embryology, 9 th ed. 2004. 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 and lateral folding at the sides of the embryo bring the endoderm inside and form the gut tube.

Cloacal membrane Langman’s Medical Embryology, 9 th ed. 2004. Folding creates the anterior and posterior intestinal portals (foregut and hindgut, respectively) The cardiac region is brought to the ventral side of the developing gut tube. Juxtaposition of ectoderm and endoderm at: Oropharyngeal (buccopharyngeal) membrane - future mouth Cloacal membrane - future anus

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

Langman’s Medical Embryology, 9 th ed. 2004. 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 to a yolk stalk

With lateral folding, mesoderm is recruited to gut wall Langman’s Medical Embryology, 9 th ed. 2004. • 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

Gut tube proper Foregut: pharynx esophagus stomach proximal duodenum Midgut: proximal duodenum to right half of transverse colon Hindgut: left half of transverse colon to anus Derivatives of gut tube thyroid parathyroid glands tympanic cavity trachea, bronchi, lungs liver, gallbladder pancreas urinary bladder (These three regions are defined by their blood supply)

25 days 32 days Langman’s Medical Embryology, 9 th ed. 2004. Celiac artery supplies the foregut Superior mesenteric artery supplies the midgut Inferior mesenteric artery supplies the hindgut

Regional patterning of the gut tube Source Undetermined Gut = bilayered tube (endoderm surrounded by mesoderm) Regional gut tube patterning and organogenesis require bi-directional endoderm-mesoderm cross-talk and inductive signals from other nearby structures

Regional patterning of the gut tube - the Hox code Hox 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 formation of major sphincters (red circles)

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

Hedgehog signaling is important for concentric (radial) patterning of the entire gut tube Source Undetermined Hh Sm. Musc. M. Velkey. Fetus Sm. Musc Wheater’s Functional Histology Adult Esophagus High Hedgehog concentration inhibits muscle formation; Low Hedgehog concentration stimulates muscle differentiation Morphogen: induces different cell fates at different concentrations of signal

Cranial-caudal pattern of the gut tube is played out as regional organ differentiation. Distinct borders form. Esophageal/Gastric border Source Undetermined Esophagus Stomach

Pyloric border (gastric/duodenal) Stomach Duodenum Source Undetermined Stomach Duod.

Regional Organogenesis: Esophagus Langman’s Medical Embryology, 9 th ed. 2004. • Region of foregut just caudal to lung bud develops into esophagus –errors in forming the esophagotracheal septa and/or recanalization 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 recanalization –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 Greater omentum Langman’s Medical Embryology, 9 th ed. 2004. • 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.

Pyloric Stenosis • Rather common malformation: present in 0. 5% - 0. 1% of infants • Characterized by very forceful (aka “projectile”), non-bilious vomiting ~1 hr. 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 Langman’s Medical Embryology, 10 th ed. 2006. • 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 ventral pancreas Langman’s Medical Embryology, 10 th ed. 2006. • 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

Once specified, the hepatoblasts proliferate and invade the septum transversum (anlage formation) Source Undetermined Angioblasts (endothelial cell precursors) are found next to the thickening 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

The dorsal pancreas is specified by signaling from the notochord Signaling from the notochord represses Shh in foregut endoderm, which permits pancreatic differentiation.

Image of ventral and dorsal pancreas removed. Original Image: Shoenwolf, et al. Larsen’s Human Embryology, 4 th Edition. 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

Development of the midgut and colon Herniation and rotation: Image of development of midgut and colon removed. Original Image: Larsen’s Human Embryology, 4 th Edition. – 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.

Defects associated with gut herniation and rotation: oomphaocoele Langman’s Medical Embryology, 9 th ed. 2004.

Defects associated with gut herniation and rotation: vitelline duct abnormalities Langman’s Medical Embryology, 9 th ed. 2004.

Defects associated with gut herniation and rotation: abnormal rotation Langman’s Medical Embryology, 10 th ed. 2006. Absent or incomplete secondary rotation Reversed primary rotation (90° CW)

Defects associated with gut herniation and rotation: volvulus Image of defects with gut herniation and rotation removed. Original Image: Carlson - Human Embryology and Developmental Biology, 4 th Edition. 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.

Development of the hindgut imperforate anus anal atresia anoperineal fistula rectovaginal fistula rectourethral fistula rectovesical fistula Langman’s Medical Embryology, 10 th ed. 2006. • 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).

Additional Source Information for more information see: http: //open. umich. edu/wiki/Citation. Policy Slide 7: Langman’s Medical Embryology, 9 th ed. 2004. Slide 8: Source Undetermined Slide 9: Langman’s Medical Embryology, 9 th ed. 2004. Slide 10: Langman’s Medical Embryology, 9 th ed. 2004. Slide 11: Langman’s Medical Embryology, 9 th ed. 2004. Slide 12: Langman’s Medical Embryology, 9 th ed. 2004. Slide 13: Langman’s Medical Embryology, 9 th ed. 2004. ; Langman’s Medical Embryology, 9 th ed. 2004. Slide 15: Langman’s Medical Embryology, 9 th ed. 2004. Slide 16: Source Undetermined Slide 17: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. Slide 18: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 19: Source Undetermined; M. Velkey; Wheater’s Functional Histology Slide 20: Source Undetermined Slide 21: Source Undetermined; Source Undetermined Slide 22: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. ; Langman’s Medical Embryology, 9 th ed. 2004. Slide 23: Langman’s Medical Embryology, 9 th ed. 2004. Slide 24: University of California, San Francisco. Slide 25: Langman’s Medical Embryology, 10 th ed. 2006. Slide 26: Langman’s Medical Embryology, 10 th ed. 2006. Slide 27: Source Undetermined Slide 28: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 29: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 30: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. Slide 31: Langman’s Medical Embryology, 9 th ed. 2004. Slide 32: Langman’s Medical Embryology, 9 th ed. 2004. Slide 33: Langman’s Medical Embryology, 10 th ed. 2006. Slide 34: Original Image Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. Slide 35: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. ; Langman’s Medical Embryology, 10 th ed. 2006.