title: Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.
abstract: 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.
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: xiaochang.zhang@childrens.harvard.edu.
authors: Xiaochang
authors: X
authors: Zhang
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Cardiology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02215, USA.
authors: Ming Hui
authors: MH
authors: Chen
authors: David H. Koch Institute for Integrative Cancer Research, Department of Biology, Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: Xuebing
authors: X
authors: Wu
authors: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Andrew
authors: A
authors: Kodani
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Jean
authors: J
authors: Fan
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Ryan
authors: R
authors: Doan
authors: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Manabu
authors: M
authors: Ozawa
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Jacqueline
authors: J
authors: Ma
authors: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The University of Tokyo, Tokyo 108-8639, Japan.
authors: Nobuaki
authors: N
authors: Yoshida
authors: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Jeremy F
authors: JF
authors: Reiter
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Douglas L
authors: DL
authors: Black
authors: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors: Peter V
authors: PV
authors: Kharchenko
authors: David H. Koch Institute for Integrative Cancer Research, Department of Biology, Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors: Phillip A
authors: PA
authors: Sharp
authors: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Neurology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
authors: Christopher A
authors: CA
authors: Walsh
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018385:Centrosome / Q000378:metabolism; D002540:Cerebral Cortex / Q000002:abnormalities / Q000166:cytology / Q000196:embryology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005091:Exons; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors
chemical_list: D003598:Cytoskeletal Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C099035:Nin protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; C573992:Ptbp1 protein, mouse; D000072260:RNA Splicing Factors; C465036:Rbfox1 protein, mouse; D038941:Polypyrimidine Tract-Binding Protein
keywords: Ninein; Ptbp1; Rbfox; filamin A; microcephaly; mother centriole; periventricular nodular heterotopia