Download or read book The Regulation and Function of the Rac1 GEF Trio and the Rac1/Cdc42 GAP CdGAP During Neuronal Development written by Jonathan DeGeer and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The wiring of the central nervous system during development supports normal physiological function and survival, and as such occurs in a tightly regulated manner. The Rho family of small GTPases are key regulators of cytoskeletal dynamics that have been implicated in neuronal development. Rho proteins are molecular switches, cycling between an inactive GDP-bound and active GTP-bound state. Oversight of Rho GTPase nucleotide cycling is performed by regulatory proteins: guanine nucleotide exchange factors (GEFs) promote GTP-bound state, while GTP hydrolysis is catalyzed by GTPase-activating proteins (GAPs). While Rho GTPase activities contribute to axon outgrowth and guidance, little is known about the spatiotemporal regulation of their cognate GEFs and GAPs. The Rac1 GEF, Trio and Rac1/Cdc42 GAP, CdGAP are highly enriched in the developing mammalian brain. Although Trio is required for the attractive axon guidance cue netrin-1 to induce axon pathfinding, the mechanisms governing Trio function are unknown. In contrast to this, the function of CdGAP in the mammalian brain is completely unknown. In this work we first explore the regulation of Trio by tyrosine phosphorylation in embryonic rat cortical neurons. Using an in vitro approach, we show that the Src-kinase Fyn phosphorylates Trio at tyrosine-2622, an event that is required for netrin-1-induced Rac1 activation. Next, we show that the molecular chaperone Hsc70 associates with Trio and the netrin-1 receptor DCC and that Hsc70 chaperone activity is required for Rac1 activation by Trio. Finally, we introduce a CdGAP-null mouse model and reveal a key role for CdGAP in vascular system development and the cytoarchitecture of cortical neurons. Overall, these studies highlight the importance of Rac1 and Cdc42 regulators during development." --