Intestinal Morphogenesis and Differentiation

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Abstract The intestine has a simple repeating architecture that is essential for its function. Absorptive villi are compartmentalized from the intestinal crypts, which house the progenitor cells and function as the stem cell niche. Recent studies have made inroads into understanding how villi form embryonically, but the cell biological mechanisms that drive the postnatal morphogenesis of crypts are not known. We have performed morphometric and dynamic transcriptomic analysis of crypt morphogenesis that has led to a framework for understanding this process. In this proposal we focus on three key stages of crypt formation and function. First, we address how the crypts become morphologically compartmentalized from the villi. Our preliminary data demonstrate that this is essential for villar patterning and maximizes surface area for absorption. Second, we analyze how crypts expand uniaxially along the crypt/villus axis in order to package progenitor cells required for the rapid turnover of the gut. Finally, as cells exit the crypt, most must become absorptive enterocytes. We will analyze functions of transcriptional regulators of enterocytes that play important roles in cell fate and tissue architecture. Together, these studies will establish how the intestinal stem cell niche forms and define roles for the stereotypical architecture in stem cell function, cell fate decisions, and tissue function.