Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex
Loss of Coiled-Coil Protein Cep55 Impairs Neural Stem Cell Abscission and Results in p53-Dependent Apoptosis in Developing Cortex
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DOI：
10.1523/jneurosci.1955-20.2021
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发表时间：
2021-04-14
影响因子：
5.3
通讯作者：
Dwyer, Noelle D.
中科院分区：
文献类型：
--
作者：
Little, Jessica N.;McNeely, Katrina C.;Dwyer, Noelle D.
为了构建大脑，胚胎神经干细胞（NSC）严格调节其细胞分裂，经历一种极化形式的胞质分裂，这种分裂形式知之甚少。细胞动力学分裂是由中间体介导的，以在顶膜处切断子细胞。在细胞系中，卷曲螺旋蛋白Cep 55被报道为是解离所需的。人类Cep 55的突变导致各种皮质畸形。然而，其在NSC专业部门中的作用尚不清楚。在这里，我们阐明了Cep 55在脑发育和脑发育中的作用。Cep 55在小鼠中的KO导致神经和非神经细胞类型的凋亡缺陷和出生后致死。大脑受到不成比例的影响，出生时患有严重的小头畸形。在固定的和活的皮质NSC中的凋亡的定量分析表明，Cep 55通过促进ESCRT募集和及时的微管分解来增加凋亡的速度和成功率。然而，大多数NSC在Cep 55不存在的情况下成功地完成了凋亡。那些失败的表现出组织特异性反应：双核神经干细胞和神经元升高p53，但双核成纤维细胞没有。这导致大脑中大量的细胞凋亡，而不是其他组织。p53和Cep 55的双KO阻断细胞凋亡，但仅部分挽救Cep 55-/-脑大小。这可能是因为持续的NSC细胞分裂缺陷和p53非依赖性的过早细胞周期退出。这项工作增加了新的证据，表明神经干细胞的调节和容错能力因细胞类型而异，在神经干细胞构建大脑时尤其重要。
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 Cep55 was reported to be required for abscission. Mutations of Cep55 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 Cep55 in abscission and brain development. KO of Cep55 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 Cep55. Those that fail show a tissue-specific response: binucleate NSCs and neurons elevate p53, but binucleate fibroblasts do not. This leads to massive apoptosis in the brain, but not other tissues. Double KO of both p53 and Cep55 blocks apoptosis but only partially rescues Cep55-/- brain size. This may be because of the persistent NSC cell division defects and p53-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.