Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain.
Prolonged Mitosis of Neural Progenitors Alters Cell Fate in the Developing Brain.
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DOI：
10.1016/j.neuron.2015.12.007
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发表时间：
2016-01-06
期刊：
影响因子：
16.2
通讯作者：
Silver DL
中科院分区：
文献类型：
--
作者：
Pilaz LJ;McMahon JJ;Miller EE;Lennox AL;Suzuki A;Salmon E;Silver DL
胚胎新皮质的发育依赖于祖细胞和神经元的平衡生产。破坏祖细胞有丝分裂的基因突变经常损害神经发生，然而有丝分裂改变和细胞命运之间的联系仍然知之甚少。在这里，我们证明了放射状神经胶质前体细胞的长时间有丝分裂直接改变了神经元的命运和后代的生存能力。对神经发生突变体MAGOH+/−的祖细胞的实时成像显示，有丝分裂延迟与优先产生神经元而不是祖细胞以及凋亡的后代显著相关。独立地，两种药理学方法揭示了有丝分裂延迟和后代命运之间的因果关系。随着有丝分裂持续时间的增加，祖细胞产生更多的凋亡或神经源性后代。我们发现细胞凋亡，但不是分化，依赖于P53，表明这些是有丝分裂延迟的不同结果。总之，我们的发现揭示了长时间的有丝分裂足以改变放射状胶质细胞后代的命运，并定义了一种新的范式来理解有丝分裂扰动是如何导致小头畸形等脑大小障碍的。
Embryonic neocortical development depends upon balanced production of progenitors and neurons. Genetic mutations disrupting progenitor mitosis frequently impair neurogenesis, however the link between altered mitosis and cell fate remains poorly understood. Here we demonstrate that prolonged mitosis of radial glial progenitors directly alters neuronal fate specification and progeny viability. Live imaging of progenitors from a neurogenesis mutant, Magoh+/−, reveals mitotic delay significantly correlates with preferential production of neurons instead of progenitors, as well as apoptotic progeny. Independently, two pharmacological approaches reveal a causal relationship between mitotic delay and progeny fate. As mitotic duration increases, progenitors produce substantially more apoptotic or neurogenic progeny. We show apoptosis, but not differentiation, is p53-dependent, demonstrating these are distinct outcomes of mitotic delay. Together our findings reveal prolonged mitosis is sufficient to alter fates of radial glia progeny and define a new paradigm to understand how mitosis perturbations underlie brain size disorders such as microcephaly.