The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation

Elife. 2014;3:e01201. doi: 10.7554/eLife.01201. Epub 2014 Jan 21.

Abstract

We show that the splicing regulator PTBP2 controls a genetic program essential for neuronal maturation. Depletion of PTBP2 in developing mouse cortex leads to degeneration of these tissues over the first three postnatal weeks, a time when the normal cortex expands and develops mature circuits. Cultured Ptbp2(-/-) neurons exhibit the same initial viability as wild type, with proper neurite outgrowth and marker expression. However, these mutant cells subsequently fail to mature and die after a week in culture. Transcriptome-wide analyses identify many exons that share a pattern of mis-regulation in the mutant brains, where isoforms normally found in adults are precociously expressed in the developing embryo. These transcripts encode proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program, where PTBP2 acts to temporarily repress expression of adult protein isoforms until the final maturation of the neuron. DOI: http://dx.doi.org/10.7554/eLife.01201.001.

Keywords: RNA binding protein; alternative splicing; gene regulation; neuronal development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Knockout Techniques
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins / metabolism*
  • Nervous System / embryology*
  • Neurons / physiology
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • Sequence Analysis, DNA

Substances

  • Nerve Tissue Proteins
  • Ptbp2 protein, mouse
  • Polypyrimidine Tract-Binding Protein

Associated data

  • GEO/GSE51740