Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality.
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.
Sasaki
Shinji
S
Department of Neuro-Science, Research Center for Genomic Medicine, Saitama Medical School, Japan. shinjih@med.osaka-cu.ac.jp
Mori
Daisuke
D
Toyo-oka
Kazuhito
K
Chen
Amy
A
Garrett-Beal
Lisa
L
Muramatsu
Masami
M
Miyagawa
Shuji
S
Hiraiwa
Noriko
N
Yoshiki
Atsushi
A
Wynshaw-Boris
Anthony
A
Hirotsune
Shinji
S
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
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