2012/07/15 by Donny D. Licatalosi, Masato Yano, John J. Fak +4 · 3 citations
Biochemistry, Genetics and Molecular Biology · Neuroscience · #RNA Research and Splicing #RNA modifications and cancer #Cancer-related molecular mechanisms research #Biology #Neurogenesis #Alternative splicing #Exon #RNA-binding protein #Cell biology #RNA splicing #Neocortex #Embryonic stem cell #Neural stem cell #Long non-coding RNA #Progenitor cell #Polypyrimidine tract-binding protein #RNA #Genetics #Stem cell #Gene #Neuroscience
paper · pdf · doi:10.1101/gad.191338.112
openalex publication_date 2012/07/15 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.