In the human brain more than 20 billion neurons become precisely connected to one another during development. How this happens, despite significant advances, remains for the most part, a mystery. Recently, we have found that the cell adhesion molecule L1 can bind directly to ezrin, radixin and moesin, members of the ERM family of molecules that link transmembrane proteins to the actin cytoskeleton. Work from other laboratories has established the importance of L1 in axon fasciculation and guidance, and our preliminary studies indicate that the ERM family plays a critical role in translating L1 binding into outgrowth. Work in non-neuronal cells suggests that ERMs act both upstream and downstream of the Rho family of small GTPases and that ERM binding to the tuberous sclerosis1 gene product, hamartin, is required for Rho mediated regulation of adhesion. This suggests that ERMs may be key regulators of actin dynamics during neural differentiation and pathfinding. The goal of the proposed work is to define the nature of ERM function in neurons, to address how ERMs are dynamically regulated in response to particular phases of neurite outgrowth and to changes in substrate, and to investigate the signaling pathways involved. The initial studies will be carried out in culture where environment can be closely controlled. Results from this work will inform the analysis and interpretation of an in vivo study of ERM function in the regulation of axon outgrowth and branching.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050634-04
Application #
7752480
Study Section
Special Emphasis Panel (ZRG1-MDCN-H (03))
Program Officer
Riddle, Robert D
Project Start
2007-01-15
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$367,074
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Carcea, Ioana; Benson, Deanna L (2017) Visualizing and Characterizing Semaphorin Endocytic Events Using Quantum Dot-Conjugated Proteins. Methods Mol Biol 1493:277-286
Carcea, Ioana; Patil, Shekhar B; Robison, Alfred J et al. (2014) Maturation of cortical circuits requires Semaphorin 7A. Proc Natl Acad Sci U S A 111:13978-83
Nikitczuk, Jessica S; Patil, Shekhar B; Matikainen-Ankney, Bridget A et al. (2014) N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo. Hippocampus 24:943-962
(2013) Retraction: Sebeo et al., Requirement for protein synthesis at developing synapses. J Neurosci 33:11324
Mintz, C David; Barrett, Kendall M S; Smith, Sarah C et al. (2013) Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a ?-aminobutyric acid type A receptor mechanism. Anesthesiology 118:825-33
Mintz, Cyrus David; Smith, Sarah C; Barrett, Kendall M S et al. (2012) Anesthetics interfere with the polarization of developing cortical neurons. J Neurosurg Anesthesiol 24:368-75
Sepulveda, B; Carcea, I; Zhao, B et al. (2011) L1 cell adhesion molecule promotes resistance to alcohol-induced silencing of growth cone responses to guidance cues. Neuroscience 180:30-40
Carcea, Ioana; Ma'ayan, Avi; Mesias, Roxana et al. (2010) Flotillin-mediated endocytic events dictate cell type-specific responses to semaphorin 3A. J Neurosci 30:15317-29
Bozdagi, Ozlem; Wang, Xiao-bin; Nikitczuk, Jessica S et al. (2010) Persistence of coordinated long-term potentiation and dendritic spine enlargement at mature hippocampal CA1 synapses requires N-cadherin. J Neurosci 30:9984-9
Sebeo, Joseph; Hsiao, Kuangfu; Bozdagi, Ozlem et al. (2009) Requirement for protein synthesis at developing synapses. J Neurosci 29:9778-93

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