(Verbatim from the applicant's description): Whereas much work has addressed the determination of apical-basal polarity in epithelia, relatively little is known about the specification of polarity orthogonal to the apical-basal axis [referred to as planar cell polarity (PCP)]. Nevertheless, PCP is integral to the function of many tissue-systems ranging from the specialized hair cells of the mammalian ear to the dynamic cilia of the tracheal and reproductive tract epithelia. Planar polarity might contribute not only to the establishment of polarized epithelial structures, but also to the ability of cells to communicate in a directional fashion. It is likely that directional signaling mechanisms are of ubiquitous importance in development. The goal of this proposal is to elucidate, using a genetically tractable system, the mechanism(s) by which signals orient the cytoskeleton of epithelial cells along an axis orthogonal to their apical-basal axes. A powerful set of genetic, molecular and phenotypic tools makes Drosophila an extremely attractive system for investigating the controls governing PCP. We will use Drosophila as our primary model system. Dissection of the signaling pathway regulating PCP has revealed roles for Frizzled and Dishevelled, thereby implicating a Wnt as ligand. Knowledge of PCP signaling will therefore also contribute to our understanding of the diversity of Wnt/Frizzled signaling mechanisms and responses. PCP signaling requires the establishment of subcellular asymmetry in response to extracellular cues. Our previous results led us to test the model that, in vivo, subcellular asymmetry in response to the PCP signal results from an asymmetric relocalization of the Dishevelled protein. Dishevelled could then serve as a marker establishing intrinsic polarity and directing the resulting cytoskeletal reorganization. Indeed, we have demonstrated asymmetric segregation of Dishevelled that is consistent with this model. This proposal describes experiments aimed at characterizing the roles of Dishevelled and other proteins in generation of an asymmetric PCP response. Specifically, the aims of this proposal are to 1) determine how asymmetric segregation of Dsh contributes to cell polarization during the PCP response, 2) identify additional components of the signaling pathway that may be involved in transducing the PCP signal, and 3) characterize some of these newly identified components.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM059823-03
Application #
6526152
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Greenberg, Judith H
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$260,953
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Kunimoto, Koshi; Bayly, Roy D; Vladar, Eszter K et al. (2017) Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic. Curr Biol 27:3120-3131.e4
Olofsson, Jessica; Axelrod, Jeffrey D (2014) Methods for studying planar cell polarity. Methods 68:97-104
Matis, Maja; Russler-Germain, David A; Hu, Qie et al. (2014) Microtubules provide directional information for core PCP function. Elife 3:e02893
Olofsson, Jessica; Sharp, Katherine A; Matis, Maja et al. (2014) Prickle/spiny-legs isoforms control the polarity of the apical microtubule network in planar cell polarity. Development 141:2866-74
Abate, Alessandro; Vincent, St├ęphane; Dobbe, Roel et al. (2012) A mathematical model to study the dynamics of epithelial cellular networks. IEEE/ACM Trans Comput Biol Bioinform 9:1607-20
Peng, Ying; Han, Chun; Axelrod, Jeffery D (2012) Planar polarized protrusions break the symmetry of EGFR signaling during Drosophila bract cell fate induction. Dev Cell 23:507-18
Stubbs, J L; Vladar, E K; Axelrod, J D et al. (2012) Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat Cell Biol 14:140-7
Vladar, Eszter K; Bayly, Roy D; Sangoram, Ashvin M et al. (2012) Microtubules enable the planar cell polarity of airway cilia. Curr Biol 22:2203-12
Matis, Maja; Axelrod, Jeffrey D; Galic, Milos (2012) A universal analysis tool for the detection of asymmetric signal distribution in microscopic images. Dev Dyn 241:1301-9
Bayly, Roy; Axelrod, Jeffrey D (2011) Pointing in the right direction: new developments in the field of planar cell polarity. Nat Rev Genet 12:385-91

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