The long-term goal of our research is to understand the molecular mechanisms by which neurons acquire their characteristic pattern of connectivity during development. Neurons are morphologically diverse cells that are specialized for communication with their elaborate dendrites designed to receive, and axons to send, information. These processes and the specificity by which they connect to each other define the functional nervous system. While recent work has demonstrated that directed growth of axons is determined by the extracellular cues, much is to be learned about how the growth cone interprets and translates these signals into fine reorganization of the cytoskeleton. Small GTP-binding proteins of the Rho subfamily, including Rho, Rac, and Cdc42, regulate the actin cytoskeleton from yeast to humans. We have previously shown that they play important and distinct roles in the morphogenesis of neurons in both flies and mammals. Our working hypothesis is that these GTP-binding proteins receive signals from cell surface receptors and in turn regulate reorganization of the cytoskeleton necessary for growth cone motility and guidance. We have recently established a genetic mosaic method to study the function of these ubiquitously expressed and pleiotropically functional genes in small populations of identified neurons in the Drosophila brain. In this application we propose to systematically investigate how Rho, Rac and Cdc42 regulate the neuronal cytoskeleton by studying genetic loss- and gain-of-function mutants in these Rho GTPases and their effector pathway components. We will also explore the potential """"""""cross talk"""""""" between these downstream effector pathways. To investigate the functions of these genes, we will use several in vivo paradigms that we have characterized, in combination with in vitro cultures. Our studies will shed light on the role of each of the Rho GTPases, how they transduce signals to the cytoskeleton, and how these signal transduction pathways interact with each other to bring about the myriad of morphological changes regulated by the Rho GTPases. Mutations in the Rho GTPase signaling pathway components have been reported in many human diseases. These include human neurological diseases such as non-syndromic mental retardation and William's syndrome, underscoring the importance of these signaling molecules in the development and function of the nervous system, and in human mental health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036623-06
Application #
6529214
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Finkelstein, Robert
Project Start
1997-08-25
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
6
Fiscal Year
2002
Total Cost
$309,586
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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