Sutton Patrick James, Mosqueda Natalie, Brownlee Christopher W
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, 11794, USA.
EMBO Rep. 2025 May 27. doi: 10.1038/s44319-025-00484-8.
Regulation of cell division orientation is a fundamental process critical to differentiation and tissue homeostasis. Microtubules emanating from the mitotic spindle pole bind a conserved complex of proteins at the cell cortex which orients the spindle and ultimately the cell division plane. Control of spindle orientation is of particular importance in developing tissues, such as the developing brain. Misorientation of the mitotic spindle and thus subsequent division plane misalignment can contribute to improper segregation of cell fate determinants in developing neuroblasts, leading to a rare neurological disorder known as microcephaly. We demonstrate that the nuclear transport protein importin α, when palmitoylated, plays a critical role in mitotic spindle orientation through localizing factors, such as NuMA, to the cell cortex. We also observe craniofacial developmental defects in Xenopus laevis when importin α palmitoylation is abrogated, including smaller head and brains, a hallmark of spindle misorientation and microcephaly. These findings characterize not only a role for importin α in spindle orientation, but also a broader role for importin α palmitoylation which has significance for many cellular processes.
细胞分裂方向的调控是一个对分化和组织稳态至关重要的基本过程。从有丝分裂纺锤体极发出的微管在细胞皮层结合一组保守的蛋白质复合物，该复合物可使纺锤体定向并最终确定细胞分裂平面。纺锤体定向的控制在发育中的组织（如发育中的大脑）中尤为重要。有丝分裂纺锤体的方向错误以及随后的分裂平面错位会导致发育中的神经母细胞中细胞命运决定因素的分离不当，从而导致一种罕见的神经系统疾病——小头畸形。我们证明，核转运蛋白输入蛋白α在棕榈酰化时，通过将诸如NuMA等定位因子定位到细胞皮层，在有丝分裂纺锤体定向中起关键作用。当输入蛋白α的棕榈酰化被消除时，我们还在非洲爪蟾中观察到颅面发育缺陷，包括头部和大脑较小，这是纺锤体方向错误和小头畸形的一个标志。这些发现不仅揭示了输入蛋白α在纺锤体定向中的作用，还表明输入蛋白α棕榈酰化在更广泛的细胞过程中具有重要意义。
