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 ␤-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.

Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity

“…For our analysis of Ndel1 level, the lack of significant SNPs tagging the Ndel1 locus indicates that Ndel1 level is likely to be a complex, perhaps polygenic, trait. Ndel1 is also essential for normal brain development and severe disruption of the protein structure or reduction on its physiological levels leads to intrauterine abortion (Sasaki et al, 2005).…”

“…Disc1/Ndel1 interaction regulates neuronal morphogenesis and positioning during neuronal integration (Duan et al, 2007). Ndel1 and Disc1 depletion in newly generated adult hippocampal neurons share characteristics including deficits in neuronal positioning (Duan et al, 2007;Kamiya et al, 2005;Sasaki et al, 2005). Ndel1 knockdown prior to the differentiation of PC12 to neuronal cells is reported to result in inhibition of neurite outgrowth, rescued by enzymatically active wild-type Ndel1, but not by a mutant form of Ndel1 (LE266/267AA) that cannot bind Disc1 (Brandon et al, 2004) or a enzymatically-inactive mutant form of Ndel1 (C273A) that can bind Disc1 (Hayashi et al, 2010).…”

The DISC locus in psychiatric illness

“…150,152 As with LIS1, mutations in NDE1 and NDEL1 cause defective neurogenesis and neuronal migration. 153,154 The role of mammalian othologues of the NUD proteins in neuronal migration may be due to their function in nuclear positioning. In mammals, nuclear positioning is critical in the process of neuronal migration, which occurs as a stepwise process.…”

“…LIS1 and NDEL1 also influence microtubule stability and organization 154,158,160,162,163 and are involved in microtubule-based transport in both anterograde and retrograde directions. 151,164 Knockdown of NDEL1 expression using RNA interference blocks neurite production, 75 which may result from defective tubulin cytoskeletal dynamics and/or deficient microtubule-based transport to the growing neurite tip.…”

Arl3 and LC8 regulate dissociation of dynactin from dynein

“…In addition, cytoplasmic dynein interacts with several proteins that do not belong to the dynein complex itself, but are crucial for adapting the motor to its cellular function including dynactin, LIS1 and NDEL1 (refs 3-5). These factors contribute to many dynein functions, and in the cases of NDEL1 and LIS1 their inhibition or depletion is phenotypically similar to a complete loss of dynein function 6,7 .…”