Roles of the Rho1 small GTPase during development in Drosophila melanogaster

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Roles of the Rho1 small GTPase during development in Drosophila melanogaster

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Title: Roles of the Rho1 small GTPase during development in Drosophila melanogaster
Author: Magie, Craig Robert
Abstract: Rho, Rac and Cdc42 are small GTPases in the Ras superfamily initially shown to regulate the actin cytoskeleton. Subsequent work linked them to many cellular processes. The diversity of functions exhibited by Rho suggests that it may operate within multiple pathways in different contexts, although how directly Rho affects these functions is not clear in all cases.We identified a mutation in Drosophila Rho1 allowing an investigation of Rho1 function in an organismal and developmental context. Interestingly, loss of Rho1 results in phenotypes distinct from those resulting from overexpression of dominant negative forms of Rho1. Zygotic Rho1 mutants exhibit severe defects in head involution and imperfect dorsal closure. Despite its dorsal closure phenotype, Rho1 does not activate genes downstream of the JNK signaling pathway or interact genetically with its components. Consistent with a role in actin cytoskeletal regulation, Rho1 interacts genetically and physically with the Drosophila formin homologue, cappuccino. Rho1 also interacts genetically and physically with concertina, a Galpha protein.Reduction of maternal Rho1 results in the disruption of the actin cytoskeleton during oogenesis, and embryos display patterning defects as a result of failure to maintain expression of the segmentation gene engrailed. Signaling by Wingless is required for maintenance of Engrailed expression. Wingless is found in vesicular structures thought to be important in the proper formation of the Wingless protein gradient. Maternal Rho1 mutants exhibit general defects in endocytic processes, resulting in a reduction of the number of Wg-positive vesicles.Rho1 is expressed ubiquitously, but accumulates at particular subcellular structures, including cadherin-based adherens junctions. Localization of cadherins and catenins, proteins involved in linking cadherins to the actin cytoskeleton, is aberrant in zygotic Rho1 mutants. Significantly, Rho1 binds directly to alpha-catenin and p120ctn in vitro and in vivo. These interactions map to distinct surface-exposed regions of the protein not previously assigned functions. These observations suggest that alpha-catenin and p120ctn are key players in a mechanism of recruiting Rho1 to its sites of action.Our data, along with recent data from other labs, suggests that Rho may be acting primarily as a cytoskeletal regulator, and its links to other cellular functions are indirect.
Description: Thesis (Ph. D.)--University of Washington, 2004

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