Date of Graduation

12-2020

Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Rachel K. Miller, Ph.D.

Committee Member

Richard Behringer, Ph.D.

Committee Member

Andrew B. Gladden, Ph.D.

Committee Member

Yoshihiro Komatsu, Ph.D.

Committee Member

Pierre D. McCrea, Ph.D.

Committee Member

Oleh M. Pochynyuk, Ph.D.

Abstract

Kidneys, like most organs in our bodies, consist of a network of epithelial tubules. Kidney tubules are called nephrons, and their morphology is important for kidney function. Nephrons develop from mesodermally derived aggregates of progenitor cells. The nephric progenitors organize into nephric tubules lined with hair-like sensory projections called cilia. Many diseases of the kidney are characterized by abnormal nephron morphology with current treatment aimed at symptom control. To understand the mechanisms underlying kidney diseases and achieve the development of novel therapies, a better understanding of how nephrons develop is needed. Although the actin cytoskeleton is critical for cell behaviors underlying nephron morphogenesis, we still know very little about the regulation of cytoskeletal dynamics. Here, we examine the role of the Wnt/Planar Cell Polarity formin, Dishevelled-associated activator of morphogenesis 1 (Daam1), in shaping nephric tubules. We show that Daam1 governs nephron morphology by regulating E-cadherin-based cell-cell adhesion of progenitor cells and junctional actin filaments' stability. We also report divergent roles for Daam1 in ciliogenesis. This dissertation enhances our understanding of cytoskeletal regulation, adhesion, and organizational behaviors involved in nephron assembly.

Keywords

Kidney, Nephron, actin, E-cadherin, Daam1, Wnt, Formin, cell adhesion

Available for download on Friday, December 17, 2021

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