The long-term goal of the research is to understand the molecular mechanism by which neurons acquire their characteristic pattern of connectivity during development. Recent evidence suggests that Rac and Cdc42, members of small GTPase of the Rho subfamily, mediate signaling from extracellular factors to the actin cytoskeleton in the regulation of neuronal arborization. The PI identified a Cdc42-binding protein, C17, in Drosophila. C17 binds to Cdc42 in a GTP-dependent manner and is highly enriched in the nervous system at the time of axonal and dendritic outgrowth. The amino third of C17 shares homology with human myotonic dystrophy protein kinase. In addition, C17 also contains domains suggestive of cytoskeletal association and regulation by other signaling molecules. The c17 mutants display defects in actin cytoskeleton and neuronal function. In this proposal, the role of C17 in the morphogenesis of neurons will be assessed by genetic interaction with other genes required in axon guidance, by biochemical studies of the regulation of its kinase activity, and by subcellular localization studies. In addition, the function of mouse C17 homolog in the morphogenesis of cerebellar Purkinje cells will be analyzed by expressing dominant negative mutants of mouse C17. Knowledge of how neurons generate axons and dendrites in development may help us understand regeneration following nerve injury. The high degree of sequence similarity between C17 and myotonic dystrophy protein kinase suggests functional similarities of the two proteins. Thus understanding the biological function C17 may shed light on the molecular pathogenesis of myotonic dystrophy, the most common adult form of muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036623-03
Application #
2892282
Study Section
Neurology C Study Section (NEUC)
Program Officer
Finkelstein, Robert
Project Start
1997-08-25
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Luo, Liqun (2007) Fly MARCM and mouse MADM: genetic methods of labeling and manipulating single neurons. Brain Res Rev 55:220-7
Scott, Ethan K; Reuter, John E; Luo, Liqun (2003) Small GTPase Cdc42 is required for multiple aspects of dendritic morphogenesis. J Neurosci 23:3118-23
Scott, Ethan K; Reuter, John E; Luo, Liqun (2003) Dendritic development of Drosophila high order visual system neurons is independent of sensory experience. BMC Neurosci 4:14
Scott, Ethan K; Raabe, Thomas; Luo, Liqun (2002) Structure of the vertical and horizontal system neurons of the lobula plate in Drosophila. J Comp Neurol 454:470-81
Winter, C G; Wang, B; Ballew, A et al. (2001) Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell 105:81-91
Liu, Z; Steward, R; Luo, L (2000) Drosophila Lis1 is required for neuroblast proliferation, dendritic elaboration and axonal transport. Nat Cell Biol 2:776-83
Lee, T; Marticke, S; Sung, C et al. (2000) Cell-autonomous requirement of the USP/EcR-B ecdysone receptor for mushroom body neuronal remodeling in Drosophila. Neuron 28:807-18
Lee, T; Winter, C; Marticke, S S et al. (2000) Essential roles of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis. Neuron 25:307-16
Lee, T; Luo, L (1999) Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22:451-61
Lee, T; Lee, A; Luo, L (1999) Development of the Drosophila mushroom bodies: sequential generation of three distinct types of neurons from a neuroblast. Development 126:4065-76

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