Background/Aims: Prenatal microcephaly is posited to arise from aberrant mitosis of neural progenitors, which disrupts both neuronal production and survival. Although microcephaly has both a genetic and environmental etiology, the mechanisms by which dysregulation of mitosis causes microcephaly are poorly understood. We previously discovered that prolonged mitosis of mouse neural progenitors, either ex vivo or in vitro, directly alters progeny cell fate, ­resulting in precocious differentiation and apoptosis. This raises questions as to whether prolonged progenitor mitosis affects cell fate and neurogenesis in vivo, and what are the underlying mechanisms? Methods/Results: Towards addressing these knowledge gaps, we developed an in vivo model of mitotic delay. This uses pharmacological inhibition to acutely and reversibly prolong mitosis during cortical development, and fluorescent dyes to label direct progeny. Using this model, we discovered that a causal relationship between mitotic delay of neural progenitors and altered progeny cell fate is evident in vivo. Using transcriptome analyses to investigate the state of delayed cells and their progeny, we uncovered potential molecular mechanisms by which prolonged mitosis induces altered cell fates, including DNA damage and p53 signaling. We then extended our studies to human neural progenitors, demonstrating that lengthened mitosis duration also directly alters neuronal cell fate. Conclusions: This study establishes a valuable new experimental paradigm towards understanding mechanisms whereby lengthened mitosis duration may explain some cases of microcephaly.
Dev Neurosci

中文翻译：

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祖先有丝分裂的急性延长影响体内皮质发育过程中的子代命运。

背景/目的：产前小头畸形是由于神经祖细胞的异常有丝分裂而引起的，它破坏了神经元的产生和存活。尽管小头畸形既有遗传病因，也有环境病因，但对有丝分裂失调导致小头畸形的机制了解甚少。我们以前发现，离体或体外小鼠神经祖细胞的有丝分裂时间会直接改变子代细胞的命运，从而导致早熟分化和凋亡。这就提出了一个问题，即延长的祖细胞有丝分裂是否会影响体内的细胞命运和神经发生，其潜在机制是什么？方法/结果：为了解决这些知识空白，我们开发了有丝分裂延迟的体内模型。这使用药理学抑制作用在皮层发育过程中急性和可逆地延长有丝分裂，并使用荧光染料标记直接后代。使用该模型，我们发现体内神经祖细胞的有丝分裂延迟与改变后代细胞命运之间存在因果关系。使用转录组分析来研究延迟细胞及其后代的状态，我们发现了潜在的分子机制，通过这种分子机制，长时间的有丝分裂会诱导改变的细胞命运，包括DNA损伤和p53信号传导。然后，我们将研究扩展到人类神经祖细胞，证明延长的有丝分裂持续时间也直接改变了神经元细胞的命运。结论：这项研究为理解机制建立了有价值的新实验范式，由此延长了有丝分裂持续时间可能解释了一些小头畸形病例。
开发神经科学