title: Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality.
abstract: Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1(-/-) mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1(-/-) blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1(+/-) mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1(cko/-)) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1(cko/+)-Ndel1(+/-) mice or Lis1(+/-)-Ndel1(+/-) mice displayed more severe neuronal migration defects than Lis1(cko/+)-Ndel1(+/)(+) mice or Lis1(+/-)-Ndel1(+/+) mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of beta-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration.
authors.affiliation: Department of Neuro-Science, Research Center for Genomic Medicine, Saitama Medical School, Japan. shinjih@med.osaka-cu.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Sasaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Mori
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Toyo-oka
authors.forename: Amy
authors.initials: A
authors.lastname: Chen
authors.forename: Lisa
authors.initials: L
authors.lastname: Garrett-Beal
authors.forename: Masami
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Shuji
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Hiraiwa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yoshiki
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D020756:Coatomer Protein / Q000378:metabolism; D020964:Embryo Loss / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D020756:Coatomer Protein; D008869:Microtubule-Associated Proteins; C486015:Ndel1 protein, mouse; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D001973:Bromodeoxyuridine