): Epithelial cells require correct polarity for their function. Their polarity and patterning is established during organogenesis. Epithelial cells are often polarized in two axes, in the apical-basolateral axis and in the plane of the epithelium. Typical examples of planar polarization include features of vertebrate skin or internal organs like the inner ear epithelium with its sensory cilia in vertebrates, and insect cuticular structures in invertebrates. The establishment of the precise polarization patterns in Drosophila serves as a paradigm to study epithelial planar polarity determination and the coordination of polarized cell shape changes in general. It is thought that planar polarization is coordinated by long range signals. The Frizzled (Fz) receptor and its signaling cascade serve as an entry point to study the molecular aspects controlling these processes. The underlying Fz signaling pathway is conserved throughout evolution and also regulates several other aspects of coordinated cellular polarization in vertebrates and invertebrates. Fz mediated planar polarity signaling is, however, distinct from the canonical Wnt Fz pathway and its components are largely unknown. Moreover, the link between Fz/planar polarity signaling and the resulting cellular responses including cytoskeletal reorganiza60n and specific transcriptional events are not understood. The scope of this application is to investigate the specific roles of newly identified genes required for planar polarity determination and cell shape change coordination. Their function in Fz signaling and/or directly in cellular polarization events will be investigated. A combination of in vivo studies in Drosophila and biochemical experiments will be utilized to achieve these goals. The process of planar polarization and Fz signaling have been linked to several medical abnormalities (including deafness in the case of the inner ear epithelium) and cancer (several components required for the process are proto-oncogenes or tumor suppressors). Thus the information acquired in this application will both advance our understanding of cellular polarization and patterning, and will also be of medical relevance, particularly for the study of carcinogenesis

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM062917-01
Application #
6319462
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
2001-07-01
Project End
2005-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$322,050
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Vega-Macaya, Franco; Manieu, Catalina; Valdivia, Mauricio et al. (2016) Establishment of the Muscle-Tendon Junction During Thorax Morphogenesis in Drosophila Requires the Rho-Kinase. Genetics 204:1139-1149
Wu, Jun; Roman, Angel-Carlos; Carvajal-Gonzalez, Jose Maria et al. (2013) Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in Drosophila. Nat Cell Biol 15:1045-55
Chin, Mei-Ling; Mlodzik, Marek (2013) The Drosophila selectin furrowed mediates intercellular planar cell polarity interactions via frizzled stabilization. Dev Cell 26:455-68
Singh, Jaskirat; Mlodzik, Marek (2012) Hibris, a Drosophila nephrin homolog, is required for presenilin-mediated Notch and APP-like cleavages. Dev Cell 23:82-96
Singh, Jaskirat; Mlodzik, Marek (2012) Planar cell polarity signaling: coordination of cellular orientation across tissues. Wiley Interdiscip Rev Dev Biol 1:479-99
Weber, Ursula; Gault, William J; Olguin, Patricio et al. (2012) Novel regulators of planar cell polarity: a genetic analysis in Drosophila. Genetics 191:145-62
Gault, William J; Olguin, Patricio; Weber, Ursula et al. (2012) Drosophila CK1-?, gilgamesh, controls PCP-mediated morphogenesis through regulation of vesicle trafficking. J Cell Biol 196:605-21
Olguin, Patricio; Glavic, Alvaro; Mlodzik, Marek (2011) Intertissue mechanical stress affects Frizzled-mediated planar cell polarity in the Drosophila notum epidermis. Curr Biol 21:236-42
Mirkovic, Ivana; Gault, William J; Rahnama, Maryam et al. (2011) Nemo kinase phosphorylates ?-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin-?-catenin. Nat Struct Mol Biol 18:665-72
Djiane, Alexandre; Mlodzik, Marek (2010) The Drosophila GIPC homologue can modulate myosin based processes and planar cell polarity but is not essential for development. PLoS One 5:e11228

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