? The Rho GTPases Cdc42, Rac, and Rho regulate cell morphology by controlling the organization of the actin cytoskeleton. While they were originally characterized in fibroblasts, they also have key roles in neuronal development. For example, they play important roles in controlling axon guidance and neurite outgrowth. Our recent work has indicated that another function of the Rho GTPases may be to control the densities and morphologies of dendritic spines. Dendritic spines are actin rich projections found on the surface of most dendrites, and they mediate most synaptic contacts in the brain. The regulation of spine density, shape, and motility is thought to have important implications for the development and function of the neocortex. The targets for the Rho GTPases that mediate changes in neuronal cell morphology are not entirely known. We have identified a new target for Cdc42 and Rac called PAK5, which is a serine/threonine kinase that is expressed primarily in the brain. We have found that PAK5 triggers filopodia formation and neurite outgrowth in neuronal cell lines. The substrates for PAK5 are unknown. The goal of this proposal is to identify PAK5 targets and regulatory proteins and to determine whether and how PAK5 and its target proteins control neuronal morphology. In the first aim we will identify molecular targets for PAK5 and proteins that interact with PAK5. In the second aim we will determine whether these proteins are part of the pathway that leads to neurite outgrowth and filopodia formation in N1E-115 cells. In the third aim we will use biolistic transfections and two photon microscopy to investigate the possible role for PAK5 in regulating the morphology, density, and motility of dendritic spines in pyramidal neurons and purkinje cells from mouse brain slices. In this aim we will also examine spine motility and structure in PAK5 knockout mice that are being generated in our lab. Overall, the results from the experiments in this proposal will help elucidate the molecular mechanisms that control neuronal cell morphology and spinogenesis, which have important repercussion for the development and function of the normal and diseased brain. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH065265-01A2
Application #
6777735
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$325,830
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Tian, Yanmei; Lei, Liang; Minden, Audrey (2011) A key role for Pak4 in proliferation and differentiation of neural progenitor cells. Dev Biol 353:206-16
Wong, Lisa Epstein; Reynolds, Albert B; Dissanayaka, Nadishani T et al. (2010) p120-catenin is a binding partner and substrate for Group B Pak kinases. J Cell Biochem 110:1244-54
Nekrasova, Tanya; Jobes, Michelle L; Ting, Jenhao H et al. (2008) Targeted disruption of the Pak5 and Pak6 genes in mice leads to deficits in learning and locomotion. Dev Biol 322:95-108