On the Developmental Patterning and Alignment of Intestinal Smooth Muscle
Huycke, Tyler Rhodes
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CitationHuycke, Tyler Rhodes. 2019. On the Developmental Patterning and Alignment of Intestinal Smooth Muscle. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe gastrointestinal (GI) tract comprises an essential system of organs required for digestion and nutrient absorption. These functions are mediated by the mechanical activities of concentric and orthogonally aligned layers of smooth muscle within the wall of the GI tract that physically induce intestinal villi formation and generate the peristaltic flow of luminal contents. While the form and functions of these muscles are well appreciated, an understanding of how each layer becomes properly patterned and aligned in the embryo is lacking and is the focus of this dissertation.
First, I describe how signaling interactions between the Hedgehog (Hh) and Bone Morphogenetic Protein (Bmp) pathways determine the concentric organization of intestinal smooth muscle. I demonstrate that the proper radial positioning of the early-forming inner circumferential muscle layer is dependent upon appropriate levels of Hh signaling, which acts in a concentration-dependent manner to activate or, through the Bmp pathway, to inhibit smooth muscle differentiation. Following its formation, this inner muscle layer as well as invading neural crest cells secrete Bmp antagonists, which locally inhibit Bmp activity within the outer mesenchyme and subsequently allow for differentiation of the later-forming outer longitudinal muscle layer.
Second, I show that alignment of the smooth muscle layers into circumferential or longitudinal orientations is dependent upon unique mechanical cues present within the developing gut as each layer differentiates. Initially, differential proliferation rates across the radial axis of the intestine generate circumferential residual strains that place the differentiating muscle cells under tension, which directs the early-forming layer to align circumferentially. Next, spontaneous contractions of this first muscle layer generate cyclic strain that guides the later-forming layer to align perpendicularly and in the longitudinal orientation, thus coupling the alignment of the second layer to that of the first. Additionally, I demonstrate that this physical mechanism can account for the helical alignment of muscles in the mouse esophagus.
Together, these studies link signaling and mechanics to explain how smooth muscle layers become patterned and aligned in the developing intestine, and, more broadly, provide a mechanistic framework for understanding the emergence of smooth muscle organization in other tubular organs.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029801
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