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Molecular and Cellular Biology, September 2005, p. 7812-7827, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7812-7827.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Complete Loss of Ndel1 Results in Neuronal Migration Defects and Early Embryonic Lethality

Shinji Sasaki,1,{dagger} Daisuke Mori,2 Kazuhito Toyo-oka,2 Amy Chen,3 Lisa Garrett-Beal,3 Masami Muramatsu,1 Shuji Miyagawa,4 Noriko Hiraiwa,5 Atsushi Yoshiki,5 Anthony Wynshaw-Boris,6 and Shinji Hirotsune1,2*

Division of Neuro-Science, Research Center for Genomic Medicine, Saitama Medical School, Yamane 1397-1, Hidaka City, Saitama 350-1241, Japan,1 Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8586, Japan,2 Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4C80, 49 Convent Dr., Bethesda, Maryland 20892,3 Division of Organ Transplantation, Biomedical Research Center, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan,4 Experimental Animal Division, Department of Biological Systems, BioResource Center, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan,5 Departments of Pediatrics and Medicine, UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Dr., Mailstop 0627, La Jolla, California 92093-06276

Received 3 March 2004/ Returned for modification 28 March 2005/ Accepted 8 June 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 (Ndel1cko/–) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1cko/+-Ndel1+/– mice or Lis1+/–-Ndel1+/– mice displayed more severe neuronal migration defects than Lis1cko/+-Ndel1+/+ mice or Lis1+/–-Ndel1+/+ mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of ß-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.

* Corresponding author. Mailing address: Department of Genetic Disease Research, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3 Abeno, Osaka 545-8586, Japan. Phone: 6-6645-3725. Fax: 6-6645-3727. E-mail: shinjih{at}med.osaka-cu.ac.jp.

{dagger} Present address: Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Molecular and Cellular Biology, September 2005, p. 7812-7827, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7812-7827.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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