ABSTRACT The nuclear membranes function as a barrier to separate the cell nucleus from the cytoplasm, but this barrier can be compromised by nuclear membrane ruptures, leading to intermixing of nuclear and cytoplasmic contents. Spontaneous nuclear membrane ruptures (i.e., ruptures occurring in the absence of mechanical stress) have been observed in cultured cells, but they are more frequent in the setting of defects or deficiencies in nuclear lamins and when cells are subjected to mechanical stress. Nuclear membrane ruptures in cultured cells have been linked to DNA damage, but the relevance of ruptures to developmental or physiologic processes in vivo has received little attention. Recently, we addressed that issue by examining neuronal migration in the cerebral cortex, a developmental process that subjects the cell nucleus to mechanical stress. In the setting of lamin B1 deficiency, we observed frequent nuclear membrane ruptures in migrating neurons in the developing cerebral cortex and showed that those ruptures are likely the cause of observed DNA damage, neuronal cell death, and profound neuropathology. In this review, we discuss the physiologic relevance of nuclear membrane ruptures, with a focus on migrating neurons in cell culture and in the cerebral cortex of genetically modified mice.

中文翻译：

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核纤层蛋白缺陷导致核膜破裂、细胞死亡和组织损伤


摘要 核膜起到将细胞核与细胞质分开的屏障的作用，但这种屏障可能会因核膜破裂而受到损害，导致核和细胞质内容物的混合。在培养的细胞中观察到自发核膜破裂（即在没有机械应力的情况下发生的破裂），但在核纤层缺陷或缺陷的情况下以及当细胞受到机械应力时更常见。培养细胞中的核膜破裂与 DNA 损伤有关，但破裂与体内发育或生理过程的相关性却很少受到关注。最近，我们通过检查大脑皮层中的神经元迁移来解决这个问题，这是一个使细胞核承受机械应力的发育过程。在核纤层蛋白 B1 缺乏的情况下，我们观察到发育中的大脑皮层中迁移神经元的频繁核膜破裂，并表明这些破裂可能是观察到的 DNA 损伤、神经元细胞死亡和深刻的神经病理学的原因。在这篇综述中，我们讨论了核膜破裂的生理相关性，重点关注细胞培养物和转基因小鼠大脑皮层中神经元的迁移。