Overlapping and non-overlapping functions of condensins I and II in neural stem cell divisions.
Overlapping and non-overlapping functions of condensins I and II in neural stem cell divisions.
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DOI：
10.1371/journal.pgen.1004847
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发表时间：
2014-12
期刊：
影响因子：
4.5
通讯作者：
Hirano T
中科院分区：
文献类型：
--
作者：
Nishide K;Hirano T
在大脑皮层发育过程中，神经干细胞（NSCs）通过对称分裂增殖，通过不对称分裂生成神经元。尽管有丝分裂染色体的忠实分离对NSC分裂至关重要，但其基本机制尚不清楚。一类进化上保守的蛋白质复合物，被称为凝聚蛋白，被认为是真核生物染色体组装和分离的核心。在这里，我们首次报道了对哺乳动物凝聚蛋白的全面遗传研究，证明了两种不同类型的凝聚蛋白复合物（凝聚蛋白I和II）对小鼠的NSC分裂和存活都是必不可少的。这两种浓缩蛋白同时缺失会导致染色体组装和分离出现严重缺陷，进而导致DNA损伤并引发p53诱导的细胞凋亡。与同时耗尽相比，浓缩蛋白I和浓缩蛋白II的单独耗尽导致NSCs的损失更慢，但它们表现出明显的有丝分裂缺陷：在浓缩蛋白II耗尽的NSCs中观察到更明显的染色体错分离，而只有在浓缩蛋白I耗尽的NSCs中才能检测到有丝分裂延迟。值得注意的是，缺乏凝缩蛋白II的NSCs显示出中心周围异染色质和核仁的超聚集，这表明凝缩蛋白II而不是凝缩蛋白I在建立间期核结构中起关键作用。有趣的是，这些缺陷被转移到有丝分裂后的神经元。我们的研究结果表明，凝聚蛋白I和II在NSCs中具有重叠和非重叠的功能，并为两种凝聚蛋白复合物的复杂平衡行为提供了进化见解。大脑皮层是由大量神经元和支持它们的细胞组成的，其中大部分来源于神经干细胞（NSCs）。NSCs通过对称分裂产生自身，通过不对称分裂产生神经元，两种类型的分裂都依赖于染色体忠实地分离成子细胞。在目前的研究中，我们研究了进化上保守的染色体调节因子，即凝缩蛋白I和凝缩蛋白II，在小鼠大脑皮层发育过程中的功能。我们发现凝缩蛋白I和II在NSC分裂和存活中具有重叠和不重叠的功能：其中任何一个凝缩蛋白的缺失都会导致染色体分离过程中明显的异常。值得注意的是，凝聚蛋白II的缺失，而不是凝聚蛋白I的缺失，也会在非分裂阶段改变染色体结构。我们的研究结果令人信服地表明，凝缩蛋白I和II之间的复杂平衡在NSC分裂中起着至关重要的作用。未来测试这两种凝缩蛋白复合物的这种平衡行为是否可能在发生不受控制的细胞分裂的致瘤性NSCs中被错误调节将是非常有趣的。
During development of the cerebral cortex, neural stem cells (NSCs) divide symmetrically to proliferate and asymmetrically to generate neurons. Although faithful segregation of mitotic chromosomes is critical for NSC divisions, its fundamental mechanism remains unclear. A class of evolutionarily conserved protein complexes, known as condensins, is thought to be central to chromosome assembly and segregation among eukaryotes. Here we report the first comprehensive genetic study of mammalian condensins, demonstrating that two different types of condensin complexes (condensins I and II) are both essential for NSC divisions and survival in mice. Simultaneous depletion of both condensins leads to severe defects in chromosome assembly and segregation, which in turn cause DNA damage and trigger p53-induced apoptosis. Individual depletions of condensins I and II lead to slower loss of NSCs compared to simultaneous depletion, but they display distinct mitotic defects: chromosome missegregation was observed more prominently in NSCs depleted of condensin II, whereas mitotic delays were detectable only in condensin I-depleted NSCs. Remarkably, NSCs depleted of condensin II display hyperclustering of pericentric heterochromatin and nucleoli, indicating that condensin II, but not condensin I, plays a critical role in establishing interphase nuclear architecture. Intriguingly, these defects are taken over to postmitotic neurons. Our results demonstrate that condensins I and II have overlapping and non-overlapping functions in NSCs, and also provide evolutionary insight into intricate balancing acts of the two condensin complexes. The cerebral cortex is built up of numerous neurons and cells supporting them, most of which originate from neural stem cells (NSCs). NSCs divide symmetrically to produce themselves and asymmetrically to generate neurons, and both types of divisions reply on faithful segregation of chromosomes into daughter cells. In the current study, we study the functions of evolutionarily conserved chromosome regulators, known as condensin I and condensin II, during development of the cerebral cortex in mice. We find that condensins I and II have both overlapping and non-overlapping functions in NSC divisions and survival: loss of either one of condensins causes distinct abnormalities in the process of chromosome segregation. Remarkably, loss of condensin II, but not of condensin I, also alters chromosome architecture during non-dividing stages. Our results demonstrate convincingly that an intricate balance between condensins I and II plays a crucial role in NSC divisions. It will be of great interest to test in the future whether such balancing acts of the two condensin complexes might be misregulated in tumorigenic NSCs that undergo uncontrolled cell divisions.