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

研究成果: Article査読

133 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1626-1642
ページ数17
ジャーナルGenes and Development
26
14
DOI
出版ステータスPublished - 2012 7月 15
外部発表はい

ASJC Scopus subject areas

  • 遺伝学
  • 発生生物学

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