Hebbar Sachin, Mesngon Mariano T, Guillotte Aimee M, Desai Bhavim, Ayala Ramses, Smith Deanna S
Department of Biological Sciences, University of South Carolina, Columbia, SC 29208, USA.
J Cell Biol. 2008 Sep 22;182(6):1063-71. doi: 10.1083/jcb.200803071.
Lis1 and Ndel1 are essential for animal development. They interact directly with one another and with cytoplasmic dynein. The developing brain is especially sensitive to reduced Lis1 or Ndel1 levels, as both proteins influence spindle orientation, neural cell fate decisions, and neuronal migration. We report here that Lis1 and Ndel1 reduction in a mitotic cell line impairs prophase nuclear envelope (NE) invagination (PNEI). This dynein-dependent process facilitates NE breakdown (NEBD) and occurs before the establishment of the bipolar spindle. Ndel1 phosphorylation is important for this function, regulating binding to both Lis1 and dynein. Prophase cells in the ventricular zone (VZ) of embryonic day 13.5 Lis1(+/-) mouse brains show reduced PNEI, and the ratio of prophase to prometaphase cells is increased, suggesting an NEBD delay. Moreover, prophase cells in the VZ contain elevated levels of Ndel1 phosphorylated at a key cdk5 site. Our data suggest that a delay in NEBD in the VZ could contribute to developmental defects associated with Lis1-Ndel1 disruption.
Lis1和Ndel1对动物发育至关重要。它们彼此直接相互作用，并与胞质动力蛋白相互作用。发育中的大脑对Lis1或Ndel1水平降低尤为敏感，因为这两种蛋白质都会影响纺锤体方向、神经细胞命运决定和神经元迁移。我们在此报告，有丝分裂细胞系中Lis1和Ndel1的减少会损害前期核膜内陷（PNEI）。这种依赖动力蛋白的过程促进核膜破裂（NEBD），并发生在双极纺锤体形成之前。Ndel1磷酸化对该功能很重要，调节与Lis1和动力蛋白的结合。胚胎第13.5天Lis1(+/-)小鼠脑室区（VZ）的前期细胞显示PNEI减少，前期细胞与前中期细胞的比例增加，提示NEBD延迟。此外，VZ中的前期细胞含有在关键的cdk5位点磷酸化的Ndel1水平升高。我们的数据表明，VZ中NEBD的延迟可能导致与Lis1-Ndel1破坏相关的发育缺陷。
