A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons

被引:160
作者
Boutz, Paul L.
Stoilov, Peter
Li, Qin
Lin, Chia-Ho
Chawla, Geetanjali
Ostrow, Kristin
Shiue, Lily
Ares, Manuel, Jr.
Black, Douglas L. [1 ]
机构
[1] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, MacDonald Res Labs 6 762, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA
[3] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[4] Univ Calif Santa Cruz, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA
关键词
alternative splicing; neuronal development; nonsense; mediated decay; polypyrimidine tract-binding proteins; splicing microarray; ultraconserved element;
D O I
10.1101/gad.1558107
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Many metazoan gene transcripts exhibit neuron-specific splicing patterns, but the developmental control of these splicing events is poorly understood. We show that the splicing of a large group of exons is reprogrammed during neuronal development by a switch in expression between two highly similar polypyrimidine tract-binding proteins, PTB and nPTB (neural PTB). PTB is a well-studied regulator of alternative splicing, but nPTB is a closely related paralog whose functional relationship to PTB is unknown. In the brain, nPTB protein is specifically expressed in post-mitotic neurons, whereas PTB is restricted to neuronal precursor cells (NPC), glia, and other nonneuronal cells. Interestingly, nPTB mRNA transcripts are found in NPCs and other nonneuronal cells, but in these cells nPTB protein expression is repressed. This repression is due in part to PTB-induced alternative splicing of nPTB mRNA, leading to nonsense-mediated decay (NMD). However, we find that even properly spliced mRNA fails to express nPTB protein when PTB is present, indicating contributions from additional post-transcriptional mechanisms. The PTB-controlled repression of nPTB results in a mutually exclusive pattern of expression in the brain, where the loss of PTB in maturing neurons allows the synthesis of nPTB in these cells. To examine the consequences of this switch, we used splicing-sensitive microarrays to identify different sets of exons regulated by PTB, nPTB, or both proteins. During neuronal differentiation, the splicing of these exon sets is altered as predicted from the observed changes in PTB and nPTB expression. These data show that the post-transcriptional switch from PTB to nPTB controls a widespread alternative splicing program during neuronal development.
引用
收藏
页码:1636 / 1652
页数:17
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