Proper elimination of synapses is critical for neuronal development and function. Dysregulation of synaptic function has been implicated in multiple developmental disorders, including Fragile X Syndrome (FXS). FXS is caused by loss-of-function mutations in the Fragile X Mental Retardation Protein (FMRP), an activity- dependent RNA-binding protein that regulates the translation of dendritically localized mRNAs. FMRP is a strong candidate to control synaptic function and/or number. Indeed, FXS patients (as well as patients with other mental retardation disorders) have an excess of dendritic spines, especially spines with an immature phenotype (Irwin et al. 2000). These defect likely results in aberrant synaptic function that is reflected as cognitive deficits. Recent data from a mouse model of FXS demonstrates an acute postsynaptic role for FMRP in CA1 hippocampal synapse elimination (Pfeiffer &Huber 2007). Potential upstream effectors of FMRP- dependent synapse elimination, specifically transcription factors that may regulate mRNAs that interact with FMRP, are unclear. However, recent data demonstrates that an activity-dependent transcription factor, myocyte enhancer factor 2 (MEF2), regulates synapse elimination in CA1 hippocampal neurons (Flavell et al. 2006). Interestingly, MEF2 has been genetically linked autism-spectrum disorders, including FXS (Morrow et al. 2008). MEF2-regulated mRNA transcripts include activity-regulated cytoskeletal protein (Arc), a protein known to regulate synaptic function;FMRP regulates Arc translation in response to activation of group I metabotropic glutamate receptors (Waung et al. 2008). Our preliminary data strongly suggest that MEF2 activity is necessary for FMRP-dependent synapse elimination and vice versa. Electrophysiology and biolistic transfection of neurons with mutant forms of FMRP will be used to determine which features of FMRP- dependent translation are necessary for MEF2-dependent synapse elimination (Specific Aim 1). Similar techniques will be utilized to investigate the role of group I mGluRs and Arc in MEF2-dependent synapse elimination (Specific Aim 2). These data provide a molecular mechanism for the increased spine density in Fragile X Syndrome and is the first to reveal deficits in MEF2-dependent function in the disease.

Public Health Relevance

Defects in neuronal communication cause cognitive deficits present in patients with autism and/or mental retardation disorders such as Fragile X syndrome. The proposed studies will investigate the role of specific proteins in regulating neuronal interactions in a mouse model of Fragile X Syndrome. The results of these experiments may lead to the development of new therapies for autism and mental retardation disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F01-L (20))
Program Officer
Urv, Tiina K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
Zip Code
Tsai, Nien-Pei; Wilkerson, Julia R; Guo, Weirui et al. (2017) FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination. Hum Mol Genet 26:293-304
Wilkerson, Julia R; Tsai, Nien-Pei; Maksimova, Marina A et al. (2014) A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell Rep 7:1589-1600
Tsai, Nien-Pei; Wilkerson, Julia R; Guo, Weirui et al. (2012) Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 151:1581-94