Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality
Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality
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DOI：
10.1128/mcb.25.17.7812-7827.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Hirotsune, S
中科院分区：
文献类型：
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作者：
Sasaki, S;Mori, D;Hirotsune, S
胞浆动力蛋白和微管动力学的调节对有丝分裂细胞分裂和神经元迁移都是至关重要的。NDEL1被鉴定为与Lis1相互作用的蛋白质，Lis1是在无脑中突变的基因的蛋白产物。为了阐明NDEL1在体内的功能，我们通过靶向基因破坏的方法在小鼠中产生了Ndel1的零等位基因和亚态等位基因。Ndel1(-/-)小鼠在着床期表现为胚胎致死性，类似于L is1和胞浆动力蛋白重链的零突变。此外，Ndel1(-/-)囊胚不能在培养中生长，内细胞团出现细胞增殖缺陷。尽管Ndel1(-/-)小鼠没有表现出明显的表型，但通过使Ndel1(CKO/-)缺失/低形态复合杂合子(Ndel1(CKO/-))进一步减少NDEL1，导致组织学缺陷与轻微的神经元迁移缺陷相一致。双Lis1(CKO/+)-Ndel1(+/-)或Lis1(+/-)-Ndel1(+/-)小鼠较Lis1(CKO/+)-Ndel1(+/-)或Lis1(+/-)-Ndel1(+/+)小鼠表现出更严重的神经元迁移缺陷。我们在Ndel1或Lis1缺失的MEF之间发现了明显的微管组织异常和类似的β-COP阳性小泡分布缺陷(以评估动力蛋白功能)，以及在Ndel1或Lis1缺失的颗粒细胞中存在类似的神经元迁移缺陷。在小鼠胚胎成纤维细胞和颗粒细胞中通过过表达Lis1、NDEL1或NDE1来挽救这些缺陷，表明NDEL1、Lis1和NDE1在调节动力蛋白的共同途径中起作用，但在微管组织和神经元迁移的调节中各有不同的作用。
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.