Department of Pediatrics, Institute for Human Genetics, Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.
Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, United States.
Elife. 2020 Mar 11;9:e51512. doi: 10.7554/eLife.51512.
Heterozygous loss of human (coding for LIS1) results in the disruption of neurogenesis and neuronal migration via dysregulation of microtubule (MT) stability and dynein motor function/localization that alters mitotic spindle orientation, chromosomal segregation, and nuclear migration. Recently, human- induced pluripotent stem cell (iPSC) models revealed an important role for LIS1 in controlling the length of terminal cell divisions of outer radial glial (oRG) progenitors, suggesting cellular functions of LIS1 in regulating neural progenitor cell (NPC) daughter cell separation. Here, we examined the late mitotic stages NPCs in vivo and mouse embryonic fibroblasts (MEFs) in vitro from -deficient mutants. -deficient neocortical NPCs and MEFs similarly exhibited cleavage plane displacement with mislocalization of furrow-associated markers, associated with actomyosin dysfunction and cell membrane hyper-contractility. Thus, it suggests LIS1 acts as a key molecular link connecting MTs/dynein and actomyosin, ensuring that cell membrane contractility is tightly controlled to execute proper daughter cell separation.
杂合性缺失导致人类 （编码 LIS1）的功能丧失，通过微管（MT）稳定性和动力蛋白马达功能/定位的失调，导致有丝分裂纺锤体取向、染色体分离和核迁移改变，从而破坏神经发生和神经元迁移。最近，人类诱导多能干细胞（iPSC）模型揭示了 LIS1 在控制外放射状胶质（oRG）祖细胞末端细胞分裂长度方面的重要作用，提示 LIS1 在调节神经祖细胞（NPC）子细胞分离中的细胞功能。在这里，我们检查了体内 -缺陷突变体的 NPC 和体外小鼠胚胎成纤维细胞（MEF）的晚期有丝分裂阶段。- 缺陷型新皮质 NPC 和 MEF 同样表现出分裂面位移，与沟道相关标记物的定位错误有关，与肌动球蛋白功能障碍和细胞膜高收缩性有关。因此，这表明 LIS1 作为一个关键的分子连接，连接 MT/动力蛋白和肌动球蛋白，确保细胞膜的收缩性得到严格控制，以执行适当的子细胞分离。
