The Role of Mechanical Forces in Patterning and Morphogenesis of the Vertebrate Gut

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The Role of Mechanical Forces in Patterning and Morphogenesis of the Vertebrate Gut

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Title: The Role of Mechanical Forces in Patterning and Morphogenesis of the Vertebrate Gut
Author: Shyer, Amy Elizabeth
Citation: Shyer, Amy Elizabeth. 2013. The Role of Mechanical Forces in Patterning and Morphogenesis of the Vertebrate Gut. Doctoral dissertation, Harvard University.
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Abstract: The vertebrate small intestine is responsible for nutrient absorption during digestion. To this end, the surface area of the gut tube is maximally expanded, both through a series of loops extending its length and via the development of a complex luminal topography. Here, I first examine the mechanism behind the formation of intestinal loops. I demonstrate that looping morphogenesis is driven by mechanical forces that arise from differential growth between the gut tube and the anchoring dorsal mesenteric sheet. A computational model based on measured parameters not only quantitatively predicts the looping pattern in chick, verifying that these physical forces are sufficient to explain the process, but also accounts for the variation in the gut looping patterns seen in other species. Second, I explore the formation of intestinal villi in chick. I find that intestinal villi form in a stepwise process as a result of physical forces generated as proliferating endodermal and mesenchymal tissues are constrained by sequentially differentiating layers of smooth muscle. A computational model incorporating measured differential growth and the geometric and physical properties of the developing chick gut recapitulates the morphological patterns seen during chick villi formation. I also demonstrate that the same basic biophysical processes underlie the formation of intestinal folds in frog and villi in mice. Finally, I focus on the process by which intestinal stem cells are ultimately localized to the base of each villus. The endoderm expresses the morphogen, Sonic hedgehog (Shh). As the luminal surface of the gut is deformed during villus formation there are resulting local maxima of Shh signaling in the mesenchyme. This results, at high threshold, in the induction of a new signaling center under the villus tip termed the villus cluster. This, in turn, feeds back to restrict proliferating progenitors in the endoderm, the presumptive precursors of the stem cells, to the base of each villus. Together, these studies provide new insight into the formation of the small intestine as a functional organ and highlight the interplay between physical forces, tissue-level growth, and signaling during development.
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:11129374
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