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

Donny D. Licatalosi, Masato Yano, John J. Fak, Aldo Mele, Sarah E. Grabinski, Chaolin Zhang, Robert B. Darnell

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

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 crosslinking 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.

Original languageEnglish
Pages (from-to)1626-1642
Number of pages17
JournalGenes and Development
Volume26
Issue number14
DOIs
Publication statusPublished - 2012 Jul 15
Externally publishedYes

Keywords

  • Alternative splicing
  • Brain development
  • HITS-CLIP
  • Neuronal progenitor
  • Polypyrimidine tract-binding protein
  • RNA-binding map

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Licatalosi, D. D., Yano, M., Fak, J. J., Mele, A., Grabinski, S. E., Zhang, C., & Darnell, R. B. (2012). Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain. Genes and Development, 26(14), 1626-1642. https://doi.org/10.1101/gad.191338.112