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Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain.

Genes & development | Jul 15, 2012

http://www.ncbi.nlm.nih.gov/pubmed/22802532

Two polypyrimidine tract RNA-binding proteins (PTBs), one near-ubiquitously expressed (Ptbp1) and another highly tissue-restricted (Ptbp2), regulate RNA in interrelated but incompletely understood ways. Ptbp1, a splicing regulator, is replaced in the brain and differentiated neuronal cell lines by Ptbp2. To define the roles of Ptbp2 in the nervous system, we generated two independent Ptbp2-null strains, unexpectedly revealing that Ptbp2 is expressed in neuronal progenitors and is essential for postnatal survival. A HITS-CLIP (high-throughput sequencing cross-linking immunoprecipitation)-generated map of reproducible Ptbp2-RNA interactions in the developing mouse neocortex, combined with results from splicing-sensitive microarrays, demonstrated that the major action of Ptbp2 is to inhibit adult-specific alternative exons by binding pyrimidine-rich sequences upstream of and/or within them. These regulated exons are present in mRNAs encoding proteins associated with control of cell fate, proliferation, and the actin cytoskeleton, suggesting a role for Ptbp2 in neurogenesis. Indeed, neuronal progenitors in the Ptbp2-null brain exhibited an aberrant polarity and were associated with regions of premature neurogenesis and reduced progenitor pools. Thus, Ptbp2 inhibition of a discrete set of adult neuronal exons underlies early brain development prior to neuronal differentiation and is essential for postnatal survival.

Pubmed ID: 22802532 RIS Download

Mesh terms: Alternative Splicing | Animals | Brain | Cell Differentiation | Exons | Heterogeneous-Nuclear Ribonucleoproteins | Mice | Mice, Mutant Strains | Nerve Tissue Proteins | Neural Stem Cells | Polypyrimidine Tract-Binding Protein | RNA, Messenger

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Associated grants

  • Agency: NIGMS NIH HHS, Id: K99GM95713
  • Agency: NINDS NIH HHS, Id: NS34389
  • Agency: NINDS NIH HHS, Id: NS40955
  • Agency: Howard Hughes Medical Institute, Id:

Mouse Genome Informatics (Data, Gene Annotation)

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