Date of Award

Fall 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics

First Advisor

Sumigray, Kaelyn

Abstract

The coordination and patterning of cells required for proper tissue architecture play a critical role in organ development and function. This process is especially important in the small intestine, which relies heavily on its unique architecture of “hills” (villi) and “valleys” (crypts) to maximize nutrient absorption. Stem cells from a single crypt generate daughter cells that migrate up the villus in a linear ribbon pattern to form villus ribbons, while progressively differentiating into zonated cell states. This differentiation is tightly correlated to distinct digestive functions through compartmentalized expression of nutrient transporters. Despite the implicit reliance of intestinal tissue physiology on tissue patterning, how villus ribbon patterning is established and maintained is not well understood. By combining in vivo mouse models and in vitro enteroid monolayer models, we found that intestinal villar cells adopted progressively linear migration paths during early postnatal development to later form villus ribbons, which is dependent on the planar cell polarity (PCP) pathway. This was accomplished through the planar orientation of basal protrusions and basement membrane proteins. Furthermore, we also found that the loss of PCP causes gross architectural defects, including villus branching, crypt translocation, and loss of epithelial cell attachment to the extracellular matrix. Our data suggest that PCP regulates directional cell migration out of the crypt and into the villus by orientation of the basal protrusions of these migrating cells. This work demonstrates that patterning has an essential role in the organization and maintenance of intestinal architecture.

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