Student Theses and Dissertations

Date of Award

2018

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Hudspeth Laboratory

Abstract

The planar orientation of mammalian cells necessitates the integration of diverse pathways. In the inner ear, at least two systems regulate the planar polarity of the hair bundle. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of each hair bundle is implemented independently by a G-protein complex comprising the alpha subunit of heterotrimeric G-protein (Gαi) and Leu-Gly-Asn repeat-enriched protein (LGN). Classically known for orienting the mitotic spindle, these proteins form an apical blueprint for hair-bundle development. Although the primary cilium also participates in each of these pathways, the mechanism that links tissue-wide and cell-intrinsic polarity is not yet understood. To address this issue, I initiated a yeast two-hybrid screen with a central component of the cell-intrinsic pathway, Gαi3. One of the most promising candidates, Dishevelled-associating protein with a high frequency of leucine residues (Daple), interacts with core PCP and cell-intrinsic signals. Here I show that Daple participates in the implementation of cell-intrinsic polarity. Regulated by G-protein signals, Daple is required for the correct positioning of the primary cilium at the apical surface. My results moreover suggest that the primary cilium or an associated structure influences the domain of Gαi3 expression that shapes the hair bundle. Daple is therefore essential to orient and pattern sensory hair bundles.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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