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Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Cell | Aug 25, 2016

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

Pubmed ID: 27565344 RIS Download

Mesh terms: Alternative Splicing | Animals | Centrosome | Cerebral Cortex | Cytoskeletal Proteins | Exons | Heterogeneous-Nuclear Ribonucleoproteins | Humans | Mice | Neural Stem Cells | Neurogenesis | Neurons | Nuclear Proteins | Polypyrimidine Tract-Binding Protein | Protein Domains | Protein Isoforms | RNA Splicing Factors

Data used in this publication

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS032457
  • Agency: NIGMS NIH HHS, Id: R01 GM049662
  • Agency: NCI NIH HHS, Id: F31 CA206236
  • Agency: NHLBI NIH HHS, Id: R01 HL131768
  • Agency: NCI NIH HHS, Id: P01 CA042063
  • Agency: NIDDK NIH HHS, Id: P30 DK098722
  • Agency: NIGMS NIH HHS, Id: R01 GM034277
  • Agency: , Id: K01 MH109747
  • Agency: NINDS NIH HHS, Id: R01 NS035129
  • Agency: NICHD NIH HHS, Id: U54 HD090255
  • Agency: NIAMS NIH HHS, Id: R01 AR054396
  • Agency: NIMH NIH HHS, Id: K01 MH109747

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