Early embryos of many metazoans polarize radially to facilitate critical patterning events such as asymmetric cell division and cellular morphogenesis. Radial polarity is established in response to cell contact patterns and functions to define the inside-outside axis of the embryo. Mammalian embryos polarize radially at compaction, and this event is thought to influence the trophectoderm versus inner cell mass cell fate decision that ensues. Recent work has implicated the PAR proteins, a highly conserved family of cell polarity regulators, in this decision, but how these proteins are regulated in the early mammalian embryo is unknown. C. elegans early embryos polarize radially prior to gastrulation when cell contacts restrict PAR proteins to contact-free cell surfaces. PAR proteins in turn regulate the asymmetric accumulation of myosin that is critical for subsequent gastrulation morphogenesis. We are using C. elegans a model system to investigate the regulation of embryonic radial polarity.
Using forward genetics, we identify a novel and conserved Rho GTPase activating protein (RhoGAP), PAC-1/ARHGAP10, which mediates C. elegans radial polarity and gastrulation by excluding PAR-6 from cell contacts. We show that PAC-1 is recruited to cell contacts, at least in part, by conserved cell adhesion molecules, and we show that PAC-1 regulates CDC-42 to control radial polarity. We propose that PAC-1 inhibits CDC-42 at cell contacts, and that CDC-42 at the contact free surface, where it is free from PAC-1 inhibition, binds and recruits PAR-6. Thus, PAC-1 provides a dynamic molecular link between the cell contacts and the PAR proteins that polarize embryos radially. Additionally, we identify genetic interactions between PAC-1 and adherens junction components, and we hypothesize that these interactions are required for epithelial integrity during epidermal morphogenesis later in development. As PAC-1 homologs exist in mammals, it will be interesting to learn if they perform orthologous functions in the control of radial polarization and morphogenesis in mammalian systems.
|Commitee:||Desplan, Claude, Lehmann, Ruth, Treisman, Jessica|
|School:||New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 72/06, Dissertation Abstracts International|
|Subjects:||Cellular biology, Developmental biology|
|Keywords:||Cell polarity, Gastrulation, PAR proteins, Radial polarity, Rho GTPase|
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