mRNA localization and regulated translation play central roles in axon guidance and synaptic plasticity. By spatially restricting gene expression within neurons, local protein synthesis allows growth cones and synapses to autonomously regulate their structure and function. The long-term goals of this project are to understand the cell biology and function of local translation during learning-related neuronal plasticity and during synapse formation. Our experiments are designed to address the following four questions: 1) what mRNAs are present in neuronal processes? 2) how do mRNAs localize within neurons? 3) how is translation of localized transcripts regulated at the synapse? and 4) what is the function of specific locally translated proteins in neurons? We address these questions in a well-characterized, experimentally tractable model of synaptogenesis and learning-related synaptic plasticity: cultured Aplysia sensory-motor neurons. Our strategy involves the use of microarray and high throughput sequencing technologies to identify mRNAs that are present in neuronal processes following neuronal stimulation, together with cell biological approaches to visualize mRNA localization and regulated translation in living neurons and RNA interference approaches to study the function of specific localized mRNAs during synapse formation and synaptic plasticity. The results of our proposed experiments will provide insight into the cell biology of mRNA localization within neurons and into the function of specific localized transcripts.

Public Health Relevance

We propose to investigate the cell biology underlying the initial wiring of the brain and the changes in brain wiring that occur during learning and memory. The results of our studies will identify genes that are likely to be involved in brain developmental disorders, such as mental retardation, and in the many diseases in which learning and memory are altered. Such diseases include Fragile X Mental Retardation, Spinal Muschular Atrophy, Alzheimer's disease, epilepsy, drug addiction and many neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045324-11
Application #
8290386
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Mamounas, Laura
Project Start
1999-09-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$330,138
Indirect Cost
$115,763
Name
University of California Los Angeles
Department
None
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Meer, Elliott J; Wang, Dan Ohtan; Kim, Sangmok et al. (2012) Identification of a cis-acting element that localizes mRNA to synapses. Proc Natl Acad Sci U S A 109:4639-44
Ho, Victoria M; Lee, Ji-Ann; Martin, Kelsey C (2011) The cell biology of synaptic plasticity. Science 334:623-8
Martin, Kelsey C; Ephrussi, Anne (2009) mRNA localization: gene expression in the spatial dimension. Cell 136:719-30
Zhao, Yali; Wang, Dan O; Martin, Kelsey C (2009) Preparation of Aplysia sensory-motor neuronal cell cultures. J Vis Exp :
Wang, Dan Ohtan; Kim, Sang Mok; Zhao, Yali et al. (2009) Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324:1536-40
Lyles, Vlasta; Zhao, Yali; Martin, Kelsey C (2006) Synapse formation and mRNA localization in cultured Aplysia neurons. Neuron 49:349-56
Poon, Michael M; Choi, Sang-Hyun; Jamieson, Christina A M et al. (2006) Identification of process-localized mRNAs from cultured rodent hippocampal neurons. J Neurosci 26:13390-9