Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Neurosci. 2013 Mar 13;33(11):4726-40. doi: 10.1523/JNEUROSCI.4191-12.2013.
Presynaptic differentiation of axons plays a fundamental role in the establishment of neuronal connectivity. However, the mechanisms that govern presynaptic differentiation in the brain remain largely to be elucidated. We report that knockdown of the transcription factor MEF2A in primary neurons and importantly in the rat cerebellar cortex in vivo robustly increases the density of orphan presynaptic sites. Remarkably, the sumoylated transcriptional repressor form of MEF2A drives the suppression of orphan presynaptic sites. We also identify the gene encoding synaptotagmin 1 (Syt1), which acts locally at presynaptic sites, as a direct repressed target gene of sumoylated MEF2A in neurons, and demonstrate that repression of Syt1 mediates MEF2A-dependent elimination of orphan presynaptic sites. Finally, we uncover a role for the MEF2A-induced elimination of orphan presynaptic sites in the accumulation of presynaptic material at large maturing presynaptic boutons. Collectively, these findings define sumoylated MEF2A and Syt1 as components of a novel cell-intrinsic mechanism that orchestrates presynaptic differentiation in the mammalian brain. Our study has important implications for understanding neuronal connectivity in brain development and disease.
轴突的突触前分化在神经元连接的建立中起着至关重要的作用。然而，大脑中控制突触前分化的机制在很大程度上仍有待阐明。我们报告称，在原代神经元中，特别是在体内的大鼠小脑皮质中，转录因子 MEF2A 的敲低会显著增加孤儿突触前位点的密度。值得注意的是，SUMO 化的转录抑制因子 MEF2A 形式驱动了孤儿突触前位点的抑制。我们还确定了编码突触结合蛋白 1（Syt1）的基因，它在突触前位点发挥局部作用，是神经元中 SUMO 化 MEF2A 的直接受抑靶基因，并证明 Syt1 的抑制介导了 MEF2A 依赖性的孤儿突触前位点的消除。最后，我们揭示了 MEF2A 诱导的孤儿突触前位点消除在成熟突触前末梢大量突触前物质积累中的作用。总的来说，这些发现定义了 SUMO 化的 MEF2A 和 Syt1 作为一种新型的细胞内机制的组成部分，该机制协调了哺乳动物大脑中的突触前分化。我们的研究对理解脑发育和疾病中的神经元连接具有重要意义。
