Cells in many tissues display polarity within the plane of the tissue. This is often called planar cell polarity (PCP) and this project focuses on the genetic, cell biological and molecular basis for PCP. Previous work funded by this grant discovered a genetic regulatory pathway for PCP in the Drosophila model system and it has been found to be conserved in vertebrates including humans. Mutations in PCP genes have been linked to a failure in neural closure, polycystic kidney disease, hearing and balance problems and heart and lung developmental defects. The pathway consists of a regulatory hierarchy, with the fz-like PCP genes being upstream of the planar polarity effector (PPE) genes which are in turn upstream of the mwh gene. The proteins that are encoded by pathway genes all accumulate asymmetrically in epithelial cells and this is thought to be essential to their function. A major goal of the application is to understand how polarity information is passed on from one group to the next in the hierarchy. A variety of genetic and biochemical experiments are designed to test models about how this is accomplished.
The second aim of the proposal is to determine the stoichiometry of proteins in the PCP complexes. An innovative microscopy approach will be taken.
The final aim i s to determine where in the PCP hierarchy a number of newly identified PCP genes function.

Public Health Relevance

The conserved PCP regulatory pathway is essential for the proper morphogenesis of a wide variety of cells, tissues and organs including the epidermis, stereocilia of the inner ear, muscle, bone, heart, lung, kidney and embryonic tissues undergoing cellular movements. Mutations of genes in this pathway have been found to be associated with a failure of neural tube closure, polycystic kidney disease, cancer and hearing and balance problems. This project is focused on understanding the function of several genes in this pathway, which could lead to potential treatments for these health problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM037163-27
Application #
8442320
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hoodbhoy, Tanya
Project Start
1986-07-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
27
Fiscal Year
2013
Total Cost
$360,426
Indirect Cost
$124,001
Name
University of Virginia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Wang, Ying; Yan, Jie; Lee, Haeryun et al. (2014) The proteins encoded by the Drosophila Planar Polarity Effector genes inturned, fuzzy and fritz interact physically and can re-pattern the accumulation of "upstream" Planar Cell Polarity proteins. Dev Biol 394:156-69
Fagan, Jeremy K; Dollar, Gretchen; Lu, Qiuheng et al. (2014) Combover/CG10732, a novel PCP effector for Drosophila wing hair formation. PLoS One 9:e107311
Adler, Paul N; Sobala, Lukasz F; Thom, Desean et al. (2013) dusky-like is required to maintain the integrity and planar cell polarity of hairs during the development of the Drosophila wing. Dev Biol 379:76-91
Lu, Qiuheng; Yan, Jie; Adler, Paul N (2010) The Drosophila planar polarity proteins inturned and multiple wing hairs interact physically and function together. Genetics 185:549-58
Fang, Xiaolan; Lu, Qiuheng; Emoto, Kazou et al. (2010) The Drosophila Fry protein interacts with Trc and is highly mobile in vivo. BMC Dev Biol 10:40
Fang, Xiaolan; Adler, Paul N (2010) Regulation of cell shape, wing hair initiation and the actin cytoskeleton by Trc/Fry and Wts/Mats complexes. Dev Biol 341:360-74
Yan, Jie; Lu, Qiuheng; Fang, Xiaolan et al. (2009) Rho1 has multiple functions in Drosophila wing planar polarity. Dev Biol 333:186-99
Taylor, Job; Adler, Paul N (2008) Cell rearrangement and cell division during the tissue level morphogenesis of evaginating Drosophila imaginal discs. Dev Biol 313:739-51
Yan, Jie; Huen, David; Morely, Terri et al. (2008) The multiple-wing-hairs gene encodes a novel GBD-FH3 domain-containing protein that functions both prior to and after wing hair initiation. Genetics 180:219-28
Ren, Nan; Charlton, Jeannette; Adler, Paul N (2007) The flare gene, which encodes the AIP1 protein of Drosophila, functions to regulate F-actin disassembly in pupal epidermal cells. Genetics 176:2223-34

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