Date of Award

12-2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Jian Zuo, Ph.D.

Committee

Kristin M. Hamre, Ph.D. Peter J. McKinnon, Ph.D. Beatriz Sosa-Pineda, Ph.D. Stanislav S. Zakharenko, Ph.D.

Keywords

hair cells, mechanoeletrical transduction channel, polycystic kidney disease, polycystin-1, stereocilia

Abstract

The polycystic kidney disease-1 (Pkd1) gene encodes a large transmembrane protein (polycystin-1 or PC-1) that is reported to function as a fluid flow-sensor in the kidney. As a member of the transient receptor potential (TRP) family, PC-1 has also been hypothesized to play a role in the elusive mechanoelectrical transduction (MET) channel in inner ear hair cells based on PC-1 role of fluid flow sensing and calcium uptake into renal epithelial cells. However, two independent mouse lines with PC-1 mutations exhibit normal MET channel function despite hearing loss and ultra-structural abnormalities of stereocilia that remain properly polarized at adult ages. These findings indicate that PC-1 plays an essential role in stereocilia structure and maintenance, but not directly in MET channel function and planar cell polarity. We also demonstrate that PC-1 is co-localized with F-actin in hair cell stereocilia as well as with the actin based microvilli in a renal epithelia cell line. These results not only provide a unique hair cell stereocilia phenotype, but also ultimately may lead to a further understanding of the mechanisms behind polycystic kidney disease.

DOI

10.21007/etd.cghs.2010.0298

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