title: Cenpj/CPAP regulates progenitor divisions and neuronal migration in the cerebral cortex downstream of Ascl1.
abstract: The proneural factor Ascl1 controls multiple steps of neurogenesis in the embryonic brain, including progenitor division and neuronal migration. Here we show that Cenpj, also known as CPAP, a microcephaly gene, is a transcriptional target of Ascl1 in the embryonic cerebral cortex. We have characterized the role of Cenpj during cortical development by in utero electroporation knockdown and found that silencing Cenpj in the ventricular zone disrupts centrosome biogenesis and randomizes the cleavage plane orientation of radial glia progenitors. Moreover, we show that downregulation of Cenpj in post-mitotic neurons increases stable microtubules and leads to slower neuronal migration, abnormal centrosome position and aberrant neuronal morphology. Moreover, rescue experiments shows that Cenpj mediates the role of Ascl1 in centrosome biogenesis in progenitor cells and in microtubule dynamics in migrating neurons. These data provide insights into genetic pathways controlling cortical development and primary microcephaly observed in humans with mutations in Cenpj.
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Garcez
authors.affiliation: Department of Biochemistry and Molecular Biology I, School of Biology and Instituto Universitario de Investigaciones Neuroquímicas (IUIN), Complutense University, 28040 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Diaz-Alonso
authors.affiliation: Department of Craniofacial Development &Stem Cell Biology, King's College London, Guy's Tower Wing, Floor 27, London SE1 9RT, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Crespo-Enriquez
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Diogo
authors.initials: D
authors.lastname: Castro
authors.affiliation: Confocal and Image Analysis Laboratory, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: Donald
authors.initials: D
authors.lastname: Bell
authors.affiliation: Division of Molecular Neurobiology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
authors.forename: François
authors.initials: F
authors.lastname: Guillemot
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division; D002465:Cell Movement; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D018274:Electroporation; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D007276:Injections, Intraventricular; D051379:Mice; D008822:Mice, Transgenic; D008867:Microtomy; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D058953:Neural Stem Cells / Q000378:metabolism* / Q000648:ultrastructure; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C499317:Ascl1 protein, mouse; C580968:Cenpj protein, mouse