Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality

Mol Cell Biol. 2005 Sep;25(17):7812-27. doi: 10.1128/MCB.25.17.7812-7827.2005.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Animals
  • Apoptosis
  • Bromodeoxyuridine
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Movement
  • Coatomer Protein / metabolism
  • Embryo Loss / embryology
  • Embryo Loss / genetics*
  • Embryo Loss / metabolism
  • Embryo Loss / pathology*
  • Gene Deletion
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism
  • Microtubules / pathology
  • Neurons / cytology*
  • Neurons / metabolism*
  • Time Factors


  • Carrier Proteins
  • Coatomer Protein
  • Microtubule-Associated Proteins
  • Ndel1 protein, mouse
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse
  • Bromodeoxyuridine