Howard Hughes Medical Institute, University of California at Los Angeles, Los Angeles, California, USA.
Nat Neurosci. 2012 Jan 15;15(3):381-8, S1. doi: 10.1038/nn.3026.
Postsynaptic density protein 95 (PSD-95) is essential for synaptic maturation and plasticity. Although its synaptic regulation has been widely studied, the control of PSD-95 cellular expression is not understood. We found that Psd-95 was controlled post-transcriptionally during neural development. Psd-95 was transcribed early in mouse embryonic brain, but most of its product transcripts were degraded. The polypyrimidine tract binding proteins PTBP1 and PTBP2 repressed Psd-95 (also known as Dlg4) exon 18 splicing, leading to premature translation termination and nonsense-mediated mRNA decay. The loss of first PTBP1 and then of PTBP2 during embryonic development allowed splicing of exon 18 and expression of PSD-95 late in neuronal maturation. Re-expression of PTBP1 or PTBP2 in differentiated neurons inhibited PSD-95 expression and impaired the development of glutamatergic synapses. Thus, expression of PSD-95 during early neural development is controlled at the RNA level by two PTB proteins whose sequential downregulation is necessary for synapse maturation.
突触后密度蛋白 95（PSD-95）对于突触成熟和可塑性至关重要。尽管其突触调节已得到广泛研究，但 PSD-95 的细胞表达调控尚不清楚。我们发现 PSD-95 在神经发育过程中受到转录后调控。在小鼠胚胎大脑中早期转录 PSD-95，但大多数其产物转录本被降解。多嘧啶tract 结合蛋白 1（PTBP1）和 PTBP2 抑制 PSD-95（也称为 Dlg4）外显子 18 的剪接，导致过早翻译终止和无意义介导的 mRNA 降解。胚胎发育过程中首先丢失 PTBP1，然后丢失 PTBP2，允许外显子 18 剪接和 PSD-95 在神经元成熟后期表达。在分化神经元中重新表达 PTBP1 或 PTBP2 会抑制 PSD-95 的表达并损害谷氨酸能突触的发育。因此，在早期神经发育过程中 PSD-95 的表达受到两种 PTB 蛋白的 RNA 水平控制，它们的顺序下调是突触成熟所必需的。
