The proposal is based on the finding that the PAR-6/aPKC complex regulates dendritic spine morphogenesis, and it does so through a novel signaling pathway involving pi90 RhoGAP and the RhoA GTPase. Studies during the mentored phase of this project revealed the small GTPase Rnd1 as a candidate protein for mediating the effects of PAR-6/aPKC on p190RhoGAP and RhoA.
Aim 1 of this proposal seeks to elucidate the molecular mechanism by which the PAR-6/aPKC complex regulates Rndl. Specifically, the effect of the PAR complex on Rndl expression and phosphorylation, and Rnd/190 interaction will be examined. To further examine the role of the PAR complex in synaptic function, we will elucidate the mechanisms by which the PAR complex regulates glutamatergic synaptic transmissioin, and identify the upstream regulators of the PAR complex. Finally, we are generating PAR-6C conditional knockout mice to test the hypothesis that the PAR complex is involved in synaptic plasticity and memory formation in vivo. My long term goal is to understand the complex signaling mechanisms regulating dendritic spine morphogenesis and synaptic plasticity, and how they translate to memory formation and maintenance in vivo.

Public Health Relevance

The goal of this research proposal is to understand the effects of a group of proteins called PAR-6 and aPKC on the way brain cells communicate with each other. The results can have significant implications in various neurological disorders including mental retardation, schizophrenia and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
4R00NS065183-03
Application #
8203101
Study Section
Special Emphasis Panel (NSS)
Program Officer
Mamounas, Laura
Project Start
2009-05-01
Project End
2013-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
3
Fiscal Year
2011
Total Cost
$249,000
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Lim, Chae-Seok; Wen, Cheng; Sheng, Yanghui et al. (2017) Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy. Small 13:
Sun, Miao; Zhang, Huaye (2017) Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1. Neurobiol Aging 60:129-140
Wu, Qian; Sun, Miao; Bernard, Laura P et al. (2017) Postsynaptic density 95 (PSD-95) serine 561 phosphorylation regulates a conformational switch and bidirectional dendritic spine structural plasticity. J Biol Chem 292:16150-16160
Lim, Chae-Seok; Kang, Xi; Mirabella, Vincent et al. (2017) BRaf signaling principles unveiled by large-scale human mutation analysis with a rapid lentivirus-based gene replacement method. Genes Dev 31:537-552
Sun, Miao; Asghar, Suwaiba Z; Zhang, Huaye (2016) The polarity protein Par3 regulates APP trafficking and processing through the endocytic adaptor protein Numb. Neurobiol Dis 93:1-11
Zhang, Huaye (2016) Polarity Determinants in Dendritic Spine Development and Plasticity. Neural Plast 2016:3145019
Bernard, Laura P; Zhang, Huaye (2015) MARK/Par1 Kinase Is Activated Downstream of NMDA Receptors through a PKA-Dependent Mechanism. PLoS One 10:e0124816
Yasuda, Kyota; Zhang, Huaye; Loiselle, David et al. (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203:737-46
Sun, Miao; Bernard, Laura P; Dibona, Victoria L et al. (2013) Calcium phosphate transfection of primary hippocampal neurons. J Vis Exp :e50808
Wu, Qian; DiBona, Victoria L; Bernard, Laura P et al. (2012) The polarity protein partitioning-defective 1 (PAR-1) regulates dendritic spine morphogenesis through phosphorylating postsynaptic density protein 95 (PSD-95). J Biol Chem 287:30781-8

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