Links between neurotrophin signals that regulate neuronal morphology and the neuronal cytoskeleton have remained elusive. In vitro, we have identified a pathway downstream of NGF involving spatially localized PI3K and GSK-3b signaling and binding of the Adenomatous Polyposis Coli protein (APC) to microtubule + ends at the growth cone. We hypothesize that this pathway mediates microtubule assembly during NGF induced axon growth. Both APC and GSK-3b are also strikingly localized to the distal axon tips and growth cones of rapidly growing axons of """"""""precondition lesioned"""""""" DRG neurons in vitro. Thus we hypothesize the GSK-3b/APC pathway mediates microtubule assembly in regenerative axon growth as well. In vivo functions of GSK-3b and APC related to nervous system development have not yet been explored because of embryonic lethality in gene targeted mice and because each has a related family member also heavily expressed in the mammalian nervous system that may have a """"""""compensatory"""""""" function. We plan to address in vivo roles of these proteins in the current proposal. We will generate inducible, DRG-specific knock-outs for GSK-3a, GSK-3b, APC, APC-L, and an upstream kinase, ILK. Using DRG specific axonal reporter mice, we will determine the roles of the GSK-3b/APC pathway in the development of peripheral and spinal cord DRG projections and in the axon regeneration normally induced by a peripheral nerve crush. If GSK-3b and APC are found to be required for assembly of microtubules during axon regeneration in vivo, and if key upstream regulators can be identified, our studies would provide a new pharmacological approach to enhancing axon regeneration after injur ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050968-02
Application #
6948471
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Mamounas, Laura
Project Start
2004-09-15
Project End
2009-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$337,625
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Neurology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ohata, Shinya; Nakatani, Jin; Herranz-PĂ©rez, Vicente et al. (2014) Loss of Dishevelleds disrupts planar polarity in ependymal motile cilia and results in hydrocephalus. Neuron 83:558-71
Morgan-Smith, Meghan; Wu, Yaohong; Zhu, Xiaoqin et al. (2014) GSK-3 signaling in developing cortical neurons is essential for radial migration and dendritic orientation. Elife 3:e02663
Xing, Lei; Newbern, Jason M; Snider, William D (2013) Neuronal development: SAD kinases make happy axons. Curr Biol 23:R720-3
Kim, Woo-Yang; Snider, William D (2011) Functions of GSK-3 Signaling in Development of the Nervous System. Front Mol Neurosci 4:44
Chen, Youjun; Tian, Xu; Kim, Woo-Yang et al. (2011) Adenomatous polyposis coli regulates axon arborization and cytoskeleton organization via its N-terminus. PLoS One 6:e24335
Kim, Yun Tai; Hur, Eun-Mi; Snider, William D et al. (2011) Role of GSK3 Signaling in Neuronal Morphogenesis. Front Mol Neurosci 4:48
Yokota, Yukako; Eom, Tae-Yeon; Stanco, Amelia et al. (2010) Cdc42 and Gsk3 modulate the dynamics of radial glial growth, inter-radial glial interactions and polarity in the developing cerebral cortex. Development 137:4101-10
Kim, Woo-Yang; Wang, Xinshuo; Wu, Yaohong et al. (2009) GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 12:1390-7
Yokota, Yukako; Kim, Woo-Yang; Chen, Youjun et al. (2009) The adenomatous polyposis coli protein is an essential regulator of radial glial polarity and construction of the cerebral cortex. Neuron 61:42-56
Zhou, Feng-Quan; Walzer, Mark; Wu, Yao-Hong et al. (2006) Neurotrophins support regenerative axon assembly over CSPGs by an ECM-integrin-independent mechanism. J Cell Sci 119:2787-96

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