Fragile X Syndrome (FXS) is the most common inherited form of mental retardation and autism identified so far. FXS is caused by transcriptional silencing or loss-of-function mutations in the Fmr1 gene, which encodes for the Fragile X mental retardation protein (FMRP). One of the most characterized phenotypes of FXS is an excess of dendritic spines, the point of contact of excitatory synapses, which links the idea that FXS results from a deficit in synapse elimination. Recent work from our laboratory demonstrated that FMRP is required for activity- dependent synapse elimination triggered by the transcription factor Myocyte Enhancer Factor 2 (MEF2;Pfeiffer et al., Neuron, 2010). The evidence suggests that FMRP functions to regulate translation or transport of MEF2 generated transcripts to mediate synapse elimination. The proposed research of this application focuses on an autism-spectrum-disorders (ASD) gene, protocadherin-10 (PCDH10) (Morrow et al., Science, 2008) and aims to characterize the mechanisms underlying MEF2- and FMRP-mediated synapse elimination by PCDH10. Our preliminary data suggests that 1) the expression of PCDH10 is regulated by MEF2 and FMRP;2) PCDH10 is involved in regulating synapse number;and 3) PCDH10 mediates ubiquitination and degradation of postsynaptic scaffold protein, PSD-95. Electrophysiology, as well as biochemical assays, will be applied to understand whether and how PCDH10 regulates PSD-95 degradation and contributes to MEF2-induced synapse elimination, which requires FMRP. The data from proposed experiments will provide molecular mechanism of MEF2- and FMRP-mediated synapse elimination as well as the function of an ASD gene in nervous system.
Synapse elimination is a critical process to maintain proper neuronal communication, which is deficient in Fragile X Syndrome (FXS), the most common known cause of autism and inherited mental retardation resulted from silencing or mutation in Fragile X mental retardation protein (FMRP). The proposed studies focus on an autism-spectrum-disorders (ASD) gene, protocadherin-10 (PCDH10), and its potential role in regulating synapse number mediated by FMRP and an upstream transcription factor, Myocyte Enhancer Factor 2 (MEF2). The results of proposed experiments will facilitate the understanding of the cause and the development of therapeutic targets of autism and mental retardation.
|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|