title: Severe NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages.
abstract: Microcephaly is a cortical malformation disorder characterized by an abnormally small brain. Recent studies have revealed severe cases of microcephaly resulting from human mutations in the NDE1 gene, which is involved in the regulation of cytoplasmic dynein. Here using in utero electroporation of NDE1 short hairpin RNA (shRNA) in embryonic rat brains, we observe cell cycle arrest of proliferating neural progenitors at three distinct stages: during apical interkinetic nuclear migration, at the G2-to-M transition and in regulation of primary cilia at the G1-to-S transition. RNAi against the NDE1 paralogue NDEL1 has no such effects. However, NDEL1 overexpression can functionally compensate for NDE1, except at the G2-to-M transition, revealing a unique NDE1 role. In contrast, NDE1 and NDEL1 RNAi have comparable effects on postmitotic neuronal migration. These results reveal that the severity of NDE1-associated microcephaly results not from defects in mitosis, but rather the inability of neural progenitors to ever reach this stage.
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Doobin
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Shahrnaz
authors.initials: S
authors.lastname: Kemal
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Tiago J
authors.initials: TJ
authors.lastname: Dantas
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Vallee
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002923:Cilia / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008831:Microcephaly / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008959:Models, Neurological; D009154:Mutation; D058953:Neural Stem Cells / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
chemical_list: D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C421108:NDEL1 protein, human; C525094:Nde1 protein, human; D034741:RNA, Small Interfering