During embryonic development, vast numbers of neurons must form connections with their proper targets. Axons are guided to their targets by growth cones, which integrate and convert guidance signals into mechanical forces required for locomotion. Movement arises from dynamic regulation of cytoskeletal polymers and associated proteins. The Ena/VASP protein family functions in various axon guidance pathways and is known to regulate the assembly of actin filaments. Ena/VASP proteins are concentrated in the tips of growth cone filopodia, where the initial response to guidance signals occurs. Several signaling pathways implicated in axon guidance regulate Ena/VASP function. Therefore, Ena/VASP proteins are well positioned to act as key convergence points between signals from guidance pathways and the actin cytoskeleton. We will test the hypothesis that Ena/VASP proteins regulate actin remodeling in response to guidance signals. We propose to examine the role of Ena/VASP in growth cone guidance and translocation using high-resolution light and electron microscopy to analyze cytoskeletal dynamics and geometry. We will also employ genetic manipulation to perturb Ena/VASP function and biochemical approaches to study Ena/VASP's role in signaling pathways. This work should yield valuable insight into how the nervous system develops and how to design methods to repair it after injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM068678-01
Application #
6673612
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Deatherage, James F
Project Start
2003-08-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$263,697
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
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Hao, Joe C; Adler, Carolyn E; Mebane, Leslie et al. (2010) The tripartite motif protein MADD-2 functions with the receptor UNC-40 (DCC) in Netrin-mediated axon attraction and branching. Dev Cell 18:950-60
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Menna, Elisabetta; Disanza, Andrea; Cagnoli, Cinzia et al. (2009) Eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PLoS Biol 7:e1000138
Kwiatkowski, Adam V; Garner, Craig C; Nelson, W James et al. (2009) Cell autonomous defects in cortical development revealed by two-color chimera analysis. Mol Cell Neurosci 41:44-50

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