The frag ile X mental re tardation protein (FMRP) binds mRNA and micro RNA, is associated with polyribosomes, and is localized in dendrites and axons. Hence, FMRP is thought to reg ulate the local translation of its mRNA targets as a means to influence neuronal development and plasticity. The lack of FMRP resu lts in dysregulated protein synthesis, wh ich is an underlying pathomechanism for the deficits in synaptic plasticity and mental impairment in frag ile X syndrome. Our long term -goal is to elucidate how FMRP controls mRNA translation and local protein synthesis du ring normal neuronal development and how FMRP deficiency leads to fragile X syndrome, the most common form of inherited mental retardation. A decade of extensive studies have characterized the biochemical interactions between FMRP and its mRNA ligands. In fact, more than 400 mRNAs have been found to associate with FMRP. However, the molecular mechanims by wh ich FMRP controls translat ion of its mRNA targets are st ill poorly understood. Moreover, how dysregulated translation , as a result of FMRP deficiency, may lead to aberrant neuronal development in the frag ile X brain remains unknown. Several lines of evidence, including our previous work, suggest that the mRNA encoding microtubule associated protein 1 B (MAP1 B) is a funct ional target of FMRP, and the lack of FMRP resu lts in dysregulated MAP1 B translation in Fmr1 KO neurons. The goal of th is proposal is to use MAP1 B as a model target of FMRP to delineate molecular mechanisms for FMRP to regulate protein synthesis in response to neuronal activation and the functional importance of FMRP-dependent trans lational regulat ion in neuronal development.
Two specific aims are proposed : 1) To del ineate how FMRP-dependent local translation of MAP1 B may control growth cone dynamics in repsonse to an axon gu idance factor and activation of group 1 metabotropic glutamate recepto r;2) To determine whether and how FMRP-mediated translat ional regu lation of MAP1 B governs projections of hippocampal mossy fiber axons during normal development and in epilepsy.

Public Health Relevance

The combination of molecular, cellular and in vivo approaches employed in this proposal will provide critical new insights into the mechanism how FMRP regulates mRNA translation and local protein synthesis that underlie neuronal network development/reconstruction, and how FMRP deficiency leads to fragile X mental syndrome. Moreover, these studies will significantly advance our knowledge on the mechanisms that control neuronal activity-regulated protein synthesis, a prevailing question in understanding the fundamental processes that govern synaptic plasticity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061344-02
Application #
7894980
Study Section
Special Emphasis Panel (ZRG1-MDCN-D (03))
Program Officer
Urv, Tiina K
Project Start
2009-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$628,226
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Lau, Anthony G; Irier, Hasan A; Gu, Jiaping et al. (2010) Distinct 3'UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF). Proc Natl Acad Sci U S A 107:15945-50