Department of Cell Biology.
Medical Scientist Training Program.
J Neurosci. 2021 Apr 14;41(15):3344-3365. doi: 10.1523/JNEUROSCI.1955-20.2021. Epub 2021 Feb 23.
To build the brain, embryonic neural stem cells (NSCs) tightly regulate their cell divisions, undergoing a polarized form of cytokinesis that is poorly understood. Cytokinetic abscission is mediated by the midbody to sever the daughter cells at the apical membrane. In cell lines, the coiled-coil protein was reported to be required for abscission. Mutations of in humans cause a variety of cortical malformations. However, its role in the specialized divisions of NSCs is unclear. Here, we elucidate the roles of in abscission and brain development. KO of in mice causes abscission defects in neural and non-neural cell types, and postnatal lethality. The brain is disproportionately affected, with severe microcephaly at birth. Quantitative analyses of abscission in fixed and live cortical NSCs show that Cep55 acts to increase the speed and success rate of abscission, by facilitating ESCRT recruitment and timely microtubule disassembly. However, most NSCs complete abscission successfully in the absence of Those that fail show a tissue-specific response: binucleate NSCs and neurons elevate , but binucleate fibroblasts do not. This leads to massive apoptosis in the brain, but not other tissues. Double KO of both and blocks apoptosis but only partially rescues brain size. This may be because of the persistent NSC cell division defects and -independent premature cell cycle exit. This work adds to emerging evidence that abscission regulation and error tolerance vary by cell type and are especially crucial in neural stem cells as they build the brain. During brain growth, embryonic neural stem cells (NSCs) must divide many times. In the last step of cell division, the daughter cell severs its connection to the mother stem cell, a process called abscission. The protein Cep55 is thought to be essential for recruiting proteins to the mother-daughter cell connection to complete abscission. We find that mutants have very small brains with disturbed structure, but almost normal size bodies. NSC abscission can occur, but it is slower than normal, and failures are increased. Furthermore, NSCs that do fail abscission activate a signal for programmed cell death, whereas non-neural cells do not. Blocking this signal only partly restores brain growth, showing that regulation of abscission is crucial for brain development.
为了构建大脑，胚胎神经干细胞（NSC）严格调节它们的细胞分裂，经历了一种尚不清楚的极化形式的胞质分裂。胞质分离是由中间体介导的，将子细胞在顶端膜处切开。在细胞系中，报道卷曲螺旋蛋白 对于胞质分离是必需的。人类中 的突变导致多种皮质畸形。然而，它在 NSC 的特化分裂中的作用尚不清楚。在这里，我们阐明了 在胞质分离和大脑发育中的作用。在小鼠中敲除 会导致神经和非神经细胞类型的胞质分离缺陷，并导致出生后死亡。大脑受到不成比例的影响，出生时出现严重的小头畸形。对固定和活皮质 NSC 中的胞质分离进行定量分析表明， Cep55 通过促进 ESCRT 募集和及时的微管解聚来增加胞质分离的速度和成功率。然而，大多数 NSC 在没有 的情况下成功完成胞质分离 那些失败的 NSC 显示出组织特异性反应：双核 NSC 和神经元上调 ，但双核成纤维细胞没有。这导致大脑中大量细胞凋亡，但其他组织没有。同时敲除 和 可以阻止凋亡，但只能部分挽救 大脑大小。这可能是由于持续的 NSC 细胞分裂缺陷和 -独立的过早细胞周期退出。这项工作增加了越来越多的证据表明，胞质分离的调节和容错性因细胞类型而异，在构建大脑的神经干细胞中尤为重要。在大脑生长过程中，胚胎神经干细胞（NSC）必须多次分裂。在细胞分裂的最后一步，子细胞切断与母干细胞的连接，这一过程称为胞质分离。蛋白 Cep55 被认为对于募集蛋白到母-子细胞连接以完成胞质分离是必需的。我们发现 突变体的大脑非常小，结构紊乱，但身体几乎正常大小。NSC 胞质分离可以发生，但比正常情况慢，失败的次数增加。此外，未能完成胞质分离的 NSC 会激活程序性细胞死亡信号，而非神经细胞则不会。阻断该信号只能部分恢复大脑生长，表明胞质分离的调节对于大脑发育至关重要。
