QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Research Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boutz, P. L. Articles by Black, D. L. Search for Related Content PubMed PubMed Citation Articles by Boutz, P. L. Articles by Black, D. L. Related Content Related Article Social Bookmarking                   What's this?

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

¹ Department of Microbiology, Immunology, and Molecular Genetics, 6-762 MacDonald Research Laboratories, Los Angeles, California 90095, USA; ² Howard Hughes Medical Institute, 6-762 MacDonald Research Laboratories, Los Angeles, California 90095, USA; ³ Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; ⁴ Sinsheimer Laboratories, Department of Molecular, Cell and Developmental Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA

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.

[Keywords: Alternative splicing; neuronal development; nonsense-mediated decay; polypyrimidine tract-binding proteins; splicing microarray; ultraconserved element]

Received April 4, 2007; revised version accepted May 16, 2007.

⁶ Corresponding author.

E-MAIL dougb{at}microbio.ucla.edu; FAX (310) 206-8623.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1558107

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation

Gabriela C. Coutinho-Mansfield, Yuanchao Xue, Yi Zhang, and Xiang-Dong Fu
Genes & Dev. 2007 21: 1573-1577. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				Z. Wang and C. B. Burge Splicing regulation: From a parts list of regulatory elements to an integrated splicing code RNA, May 1, 2008; 14(5): 802 - 813. [Abstract] [Full Text] [PDF]

				E. V. Makeyev and T. Maniatis Multilevel Regulation of Gene Expression by MicroRNAs Science, March 28, 2008; 319(5871): 1789 - 1790. [Abstract] [Full Text] [PDF]

				M. J. Moore and P. A. Silver Global analysis of mRNA splicing RNA, February 1, 2008; 14(2): 197 - 203. [Abstract] [Full Text] [PDF]

				C. Ben-Dov, B. Hartmann, J. Lundgren, and J. Valcarcel Genome-wide Analysis of Alternative Pre-mRNA Splicing J. Biol. Chem., January 18, 2008; 283(3): 1229 - 1233. [Abstract] [Full Text] [PDF]

				C. E. Johnson, Y. Y. Huang, A. B. Parrish, M. I. Smith, A. E. Vaughn, Q. Zhang, K. M. Wright, T. Van Dyke, R. J. Wechsler-Reya, S. Kornbluth, et al. Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues PNAS, December 26, 2007; 104(52): 20820 - 20825. [Abstract] [Full Text] [PDF]

				G. C. Coutinho-Mansfield, Y. Xue, Y. Zhang, and X.-D. Fu PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation Genes & Dev., July 1, 2007; 21(13): 1573 - 1577. [Full Text] [PDF]