Date of Award

Spring 1-1-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology, Molecular Biology and Biochemistry

First Advisor

Leslie A. Leinwand

Second Advisor

Rui Yi

Third Advisor

Min Han

Fourth Advisor

Xiao-jing Wang

Fifth Advisor

Zhe Chen

Abstract

The microRNA-200 (miR-200) family is well known for preventing epithelial-to-mesenchymal transition in cancer. However, the targets and functions of this family in normal epithelial tissues remain unclear. This five-member microRNA (miRNA) family also presents a unique platform for studying miRNA-mediated regulation, as they share two nearly-identical seed sequences. The results presented within this dissertation establish a role for these miRNAs in governing hair follicle morphogenesis and fine-tuning cell specification by regulating cell adhesion, polarity, and signaling pathways. By directly ligating miRNAs to their targeted mRNA regions, numerous miR-200 family targets are identified, many of which are involved in the regulation of focal adhesions, actin cytoskeleton, cell cycle and Hippo/Yap signaling. In addition, the experiments presented within this dissertation show that members of the miR-200 family interact with some unique genes, but that they also frequently share targets. Mouse models for miR-200 over-expression and loss-of-function show that the miR-200 family regulates cell adhesion, polarity and reduces cell division, leading to precise cell fate specification and hair morphogenesis. These findings demonstrate that combinatorial targeting of many genes is critical for miR-200 family functions, and provide new insights into this family’s functions in the developing skin and hair follicle.

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