Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain.
Genes Dev
; 26(14): 1626-42, 2012 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-22802532
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 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
RNA, Messenger
/
Cell Differentiation
/
Alternative Splicing
/
Polypyrimidine Tract-Binding Protein
/
Neural Stem Cells
/
Nerve Tissue Proteins
Limits:
Animals
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2012
Document type:
Article
Affiliation country:
United States