05.28.09(a): Development of the Gastrointestinal System

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  • Fig 13.3
  • Fig 13.14
  • Shh is expressed throughout the endoderm beginning at the time of portal formation Sonic in the endoderm is responsible for inducing other genes in the mesoderm. For example, Shh induces BMP4 in the mesoderm. But this induction is regional and does not occur in the stomach. BMP inhibits proliferation of muscle; ectopic expression of BMP4 in the stomach mesoderm makes the stomach muscle look like intestinal muscle, much less robust. Therefore, the restriction of BMP4 expression from the stomach seems to be important for stomach muscle formation. But this is temporally restricted, because very early on, BMP4 IS expressed in the stomach and this is required for pyloric sphincter formation. Shh also induces the expression of Hox genes in the mesoderm. For example, it induces Hoxd13 in the hindgut, but not the midgut. However, ectopic expression of Hoxd13 in the midgut makes the endoderm develop like hindgut. It is not clear why only hindgut mesoderm is competent to express hoxd13 in response to the Shh signal.
  • In the gut, the Hh signal also plays a key patterning role. Both Shh and Ihh are expressed early in the endodermal tube of the developing intestine, forming a concentration gradient. Here the Hh signal is critical for radial patterning of mesenchymal structures of the gut. Mostly from studies in the developing Chick, it was shown that Shh induces Bmp4 in adjacent mesenchyme, which then controls growth of stroma and smooth muscle. Shh is also critical for establishment of smooth muscle and neuronal populations, but only in the outer regions of the gut tube. This patterning effect is due to the inhibition of these structures at higher concentrations of Shh, closer to the endodermal tube. Later in development, after villus formation, Shh and Ihh expression becomes confined to the intervillus region of the epithelium, and subsequent epithelial crypt compartment. The role of the Hh signal in this location during late intesintal development is currently unknown.
  • Endothelial cells also are required for pancreas formation and in the development of the glandular stomach and lung. It is not known where these cells come from, are they recruited, or are they converted form local mesencymal precursors. The liver spends most of its fetal life being a site for hematopoiesis, so the relationship between vascular and hematopoietic development and liver development is a continuing one.
  • 05.28.09(a): Development of the Gastrointestinal System

    1. 1. 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_address] 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.
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    3. 3. Development of the Gastrointestinal System Matt Velkey Spring 2009
    4. 4. <ul><li>General outline/learning objectives: </li></ul><ul><li>Formation of the gut tube - morphogenic events </li></ul><ul><li>Cranial/caudal patterning of the gut tube </li></ul><ul><li>Radial patterning of the gut tube </li></ul><ul><li>*Regional patterning: Formation of intestinal villi* </li></ul><ul><li>Organogenesis: Inductive events in formation of </li></ul><ul><li>gut-associated organs (liver, pancreas) </li></ul><ul><li>Suggested reading: Sadler, Chapter 14 </li></ul>
    5. 5. <ul><li>Major themes: </li></ul><ul><li>Regional patterning and cell movements set the stage for </li></ul><ul><li>a series of inductive events that form organs: </li></ul><ul><ul><li>Importance of cell-cell communication </li></ul></ul><ul><ul><li>Competency and/or signals may be regionally </li></ul></ul><ul><li>and/or temporally limited. </li></ul>Factors that control proliferation/differentiation during organogenesis may be later associated with carcinogenesis (Sonic Hedgehog, Shh) <ul><li>There are distinct stages in organ formation: </li></ul><ul><ul><li>Specification </li></ul></ul><ul><ul><li>Anlage (bud) formation </li></ul></ul><ul><ul><li>Proliferation </li></ul></ul><ul><ul><li>Differentiation </li></ul></ul>
    6. 6. <ul><li>Vocabulary: </li></ul><ul><ul><li>Competency: The ability of a cell or group of cells to respond to a particular signal </li></ul></ul><ul><ul><li>Endoderm : layer of post-gastrulation embryo that gives rise to the epithelium of the gut tube and gut-derived organs </li></ul></ul><ul><ul><li>Mesoderm/Mesenchyme : layer of post-gastrulation embryo that gives rise to the surrounding tissue of the gut tube </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Sonic Hedgehog (Shh) : secreted signaling molecule made by the endoderm; important in organ-specific development </li></ul></ul><ul><ul><li>BMPs, FGFs: Secreted signaling molecules important in liver and pancreas specification </li></ul></ul>
    7. 7. 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.
    8. 8. Early mesodermal patterning: (buccopharyngeal membrane) Specific regions of the epiblast migrate through the streak at different levels and assume different positions within the embryo: Source Undetermined Cranial to caudal: Notochord (n) Paraxial mesoderm (pm) Intermediate mesoderm (im) * Lateral plate mesoderm (lpm) Extraembryonic mesoderm (eem)
    9. 9. 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. Endoderm Langman’s Medical Embryology, 9th ed. 2004.
    10. 10. 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. Cloacal membrane Langman’s Medical Embryology, 9th ed. 2004. Juxtaposition of ectoderm and endoderm at: Oropharyngeal (buccopharyngeal) membrane - future mouth Cloacal membrane - future anus
    11. 11. 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, 9th ed. 2004.
    12. 12. 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 Langman’s Medical Embryology, 9th ed. 2004.
    13. 13. With lateral folding, mesoderm is recruited to gut wall <ul><li>Lateral folding of the embryo completes the gut tube </li></ul><ul><li>Mesodermal layer of the gut tube is called splanchnic (visceral) mesoderm - derived from lateral plate mesoderm </li></ul><ul><li>Somatic mesoderm lines body cavity </li></ul>Langman’s Medical Embryology, 9th ed. 2004. Langman’s Medical Embryology, 9 th ed. 2004.
    14. 14. Foregut: pharynx thyroid esophagus parathyroid glands stomach tympanic cavity proximal duodenum trachea, bronchi, lungs liver, gallbladder pancreas Midgut: proximal duodenum to right half of transverse colon Hindgut: left half of urinary bladder transverse colon to anus Gut tube proper Derivatives of gut tube (These three regions are defined by their blood supply)
    15. 15. 25 days 32 days Celiac artery supplies the foregut Superior mesenteric artery supplies the midgut Inferior mesenteric artery supplies the hindgut Langman’s Medical Embryology, 9 th ed. 2004.
    16. 16. 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 Source Undetermined
    17. 17. Regional patterning of the gut tube - the Hox code <ul><li>Hox genes are evolutionarily conserved transcription factors that are used in regional patterning (flies to mammals). </li></ul><ul><li>The gut has an cranial-caudal Hox gene expression pattern (code) similar to that seen in neural tissue. </li></ul><ul><li>Some Hox genes are expressed in mesoderm, in overlapping patterns; some are expressed in endoderm. </li></ul><ul><li>Hox gene expression boundaries correspond to morphologically recognizable elements in the GI tract. </li></ul><ul><li>Hox gene expression is important for formation of major sphincters (red circles) </li></ul>
    18. 18. <ul><li>Regulatory networks in time and space: </li></ul><ul><li>Regional variation in regulatory pathways due to: </li></ul><ul><li>Regional variation in competence (induction of mesodermal Hoxd-13 by Shh) </li></ul><ul><li>Temporal variation in signaling (restriction of BMP from stomach mesoderm) </li></ul>How is the patterning established? How does it play out in regional organogenesis? The role of Sonic hedgehog (Shh) in gut patterning….
    19. 19. Hedgehog signaling is important for concentric (radial) patterning of the entire gut tube Morphogen: induces different cell fates at different concentrations of signal Source Undetermined Wheater’s Functional Histology M. Velkey. Hh Fetus High Hedgehog concentration inhibits muscle formation; Sm. Musc. Sm. Musc Low Hedgehog concentration stimulates muscle differentiation Adult Esophagus
    20. 20. Esophageal/Gastric border Esophagus Stomach Cranial-caudal pattern of the gut tube is played out as regional organ differentiation. Distinct borders form. Source Undetermined
    21. 21. Pyloric border (gastric/duodenal) Stomach Duod. Stomach Duodenum Source Undetermined Source Undetermined
    22. 22. Regional Organogenesis: Esophagus <ul><li>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. </li></ul><ul><li>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 </li></ul><ul><ul><li>NOTE: this process of recanalization occurs throughout the gut tube, so occlusion can occur anywhere along the GI tract (e.g. duodenal stenosis) </li></ul></ul><ul><li>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. </li></ul>Langman’s Medical Embryology, 9 th ed. 2004.
    23. 23. Regional Organogenesis: Stomach <ul><li>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). </li></ul><ul><li>Differential growth occurs to establish the greater and lesser curvatures </li></ul><ul><li>Unlike other parts of the gut tube, the dorsal AND ventral mesenteries are retained to become the greater and lesser omenta, respectively </li></ul><ul><li>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. </li></ul>Greater omentum Langman’s Medical Embryology, 9 th ed. 2004.
    24. 24. Pyloric Stenosis <ul><li>Rather common malformation: present in 0.5% - 0.1% of infants </li></ul><ul><li>Characterized by very forceful (aka “projectile”), non-bilious vomiting ~1hr. after feeding (when pyloric emptying would occur). </li></ul><ul><ul><li>NOTE: the presence of bile would indicate POST-duodenal blockage of some sort. </li></ul></ul><ul><li>Hypertrophied sphincter can often be palpated as a spherical nodule; peristalsis of the sphincter seen/felt under the skin. </li></ul><ul><li>Stenosis is due to overproliferation / hypertrophy of pyloric sphincter… NOT an error in re-canalization. </li></ul><ul><li>More common in males than females, so most likely has a genetic basis which is as yet undetermined. </li></ul>University of California, San Francisco.
    25. 25. Regional Organogenesis: Liver & Pancreas <ul><li>Liver and pancreas arise from foregut endoderm in response to signals from nearby mesoderm </li></ul><ul><li>Pancreas actually has ventral and dorsal components, each specified in a different manner </li></ul>Langman’s Medical Embryology, 10 th ed. 2006.
    26. 26. Cardiac mesoderm and septum transversum specifies liver <ul><li>FGFs secreted by cardiac mesoderm and BMPs secreted by septum transversum induce liver from foregut endoderm </li></ul><ul><li>Endoderm just caudal to liver bud is out of reach from these signals and develops into pancreas </li></ul>ventral pancreas Langman’s Medical Embryology, 10 th ed. 2006.
    27. 27. Once specified, the hepatoblasts proliferate and invade the septum transversum 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 (anlage formation) Source Undetermined
    28. 28. The dorsal pancreas is specified by signaling from the notochord <ul><li>Signaling from the notochord represses Shh in foregut endoderm, which permits pancreatic differentiation. </li></ul>
    29. 29. Rotation of the duodenum brings the ventral and dorsal pancreas together <ul><li>Aberrations in this process may result in an annular pancreas , which can constrict the duodenum </li></ul>Original Image: Shoenwolf, et al. Larsen’s Human Embryology, 4th Edition. Image of ventral and dorsal pancreas removed.
    30. 30. Development of the midgut and colon <ul><li>Herniation and rotation: </li></ul><ul><ul><li>Growth of the GI tract exceeds volume of abdominal cavity so the tube herniates through umbilicus </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>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) </li></ul></ul><ul><ul><li>Once in the abdominal cavity, the colon continues to grow in length, pushing the appendix to its final position in the lower right quadrant. </li></ul></ul>Original Image: Larsen’s Human Embryology, 4th Edition. Image of development of midgut and colon removed.
    31. 31. Defects associated with gut herniation and rotation: oomphaocoele Langman’s Medical Embryology, 9 th ed. 2004.
    32. 32. Defects associated with gut herniation and rotation: vitelline duct abnormalities Langman’s Medical Embryology, 9 th ed. 2004.
    33. 33. Defects associated with gut herniation and rotation: abnormal rotation Absent or incomplete secondary rotation Reversed primary rotation (90° CW) Langman’s Medical Embryology, 10 th ed. 2006.
    34. 34. 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. Original Image: Carlson - Human Embryology and Developmental Biology, 4th Edition. Image of defects with gut herniation and rotation removed.
    35. 35. Development of the hindgut <ul><li>Derivatives of the hindgut include everything caudal to the distal 1/3 of the transverse colon. </li></ul><ul><li>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) </li></ul><ul><li>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). </li></ul>anal atresia imperforate anus anoperineal fistula rectovaginal fistula rectourethral fistula rectovesical fistula Langman’s Medical Embryology, 10 th ed. 2006.
    36. 36. <ul><li>Slide 7: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 8: Source Undetermined </li></ul><ul><li>Slide 9: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 10: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 11: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 12: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 13: Langman’s Medical Embryology, 9th ed. 2004.; Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 15: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 16: Source Undetermined </li></ul><ul><li>Slide 17: Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 18: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 19: Source Undetermined; M. Velkey; Wheater’s Functional Histology </li></ul><ul><li>Slide 20: Source Undetermined </li></ul><ul><li>Slide 21: Source Undetermined; Source Undetermined </li></ul><ul><li>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. </li></ul><ul><li>Slide 23: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 24: University of California, San Francisco. </li></ul><ul><li>Slide 25: Langman’s Medical Embryology, 10th ed. 2006. </li></ul><ul><li>Slide 26: Langman’s Medical Embryology, 10th ed. 2006. </li></ul><ul><li>Slide 27: Source Undetermined </li></ul><ul><li>Slide 28: Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 29: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 30: Original Image Schoenwolf et al: Larsen’s Human Embryology, 4 th Edition. Copyright 2008 Churchill Livingston, an imprint of Elsevier, Inc. </li></ul><ul><li>Slide 31: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 32: Langman’s Medical Embryology, 9th ed. 2004. </li></ul><ul><li>Slide 33: Langman’s Medical Embryology, 10th ed. 2006. </li></ul><ul><li>Slide 34: Original Image Carlson: Human Embryology and Developemental Biology, 4 th Edition. Copyright 2009 by Mosby, an imprint of Elsevier, Inc. </li></ul><ul><li>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. </li></ul>Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy

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