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A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.
Genes Dev. 2007 Jul 01; 21(13):1636-52.GD

Abstract

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.

Authors+Show Affiliations

Department of Microbiology, Immunology, and Molecular Genetics, 6-762 MacDonald Research Laboratories, Los Angeles, CA 90095, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17606642

Citation

Boutz, Paul L., et al. "A Post-transcriptional Regulatory Switch in Polypyrimidine Tract-binding Proteins Reprograms Alternative Splicing in Developing Neurons." Genes & Development, vol. 21, no. 13, 2007, pp. 1636-52.
Boutz PL, Stoilov P, Li Q, et al. A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev. 2007;21(13):1636-52.
Boutz, P. L., Stoilov, P., Li, Q., Lin, C. H., Chawla, G., Ostrow, K., Shiue, L., Ares, M., & Black, D. L. (2007). A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes & Development, 21(13), 1636-52.
Boutz PL, et al. A Post-transcriptional Regulatory Switch in Polypyrimidine Tract-binding Proteins Reprograms Alternative Splicing in Developing Neurons. Genes Dev. 2007 Jul 1;21(13):1636-52. PubMed PMID: 17606642.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. AU - Boutz,Paul L, AU - Stoilov,Peter, AU - Li,Qin, AU - Lin,Chia-Ho, AU - Chawla,Geetanjali, AU - Ostrow,Kristin, AU - Shiue,Lily, AU - Ares,Manuel,Jr AU - Black,Douglas L, PY - 2007/7/4/pubmed PY - 2007/8/19/medline PY - 2007/7/4/entrez SP - 1636 EP - 52 JF - Genes & development JO - Genes Dev. VL - 21 IS - 13 N2 - 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. SN - 0890-9369 UR - https://www.unboundmedicine.com/medline/citation/17606642/A_post_transcriptional_regulatory_switch_in_polypyrimidine_tract_binding_proteins_reprograms_alternative_splicing_in_developing_neurons_ L2 - http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=17606642 DB - PRIME DP - Unbound Medicine ER -