Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell. 2012 Dec 21;151(7):1581-94. doi: 10.1016/j.cell.2012.11.040.
The activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination.
活性依赖性转录因子肌细胞增强因子 2（MEF2）诱导小鼠神经元中兴奋性突触消除，这需要脆性 X 智力迟钝蛋白（FMRP），一种与人类认知功能障碍和自闭症相关的 RNA 结合蛋白。我们在这里报告，原钙黏蛋白 10（Pcdh10），一种自闭症谱系障碍基因，是这个过程所必需的。MEF2 和 FMRP 合作调节 Pcdh10 的表达。在 MEF2 激活后，PSD-95 被泛素 E3 连接酶鼠双微体 2（Mdm2）泛素化，然后与 Pcdh10 结合，将其与蛋白酶体连接进行降解。阻断 Pcdh10-蛋白酶体相互作用可抑制 MEF2 诱导的 PSD-95 降解和突触消除。在缺乏 FMRP 的神经元中，真核翻译延伸因子 1α（EF1α）的蛋白水平升高，EF1α 是 Mdm2 相互作用蛋白和 FMRP 靶 mRNA，它将 Mdm2 隔离并阻止 MEF2 诱导的 PSD-95 泛素化和突触消除。总之，我们的发现揭示了多个自闭症相关基因在活性依赖性突触消除中的作用。
