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Time is of the essence: the molecular mechanisms of primary microcephaly
Genes & Development ( IF 10.5 ) Pub Date : 2021-12-01 , DOI: 10.1101/gad.348866.121
Thao P Phan 1 , Andrew J Holland 1
Affiliation  

Primary microcephaly is a brain growth disorder characterized by a severe reduction of brain size and thinning of the cerebral cortex. Many primary microcephaly mutations occur in genes that encode centrosome proteins, highlighting an important role for centrosomes in cortical development. Centrosomes are microtubule organizing centers that participate in several processes, including controlling polarity, catalyzing spindle assembly in mitosis, and building primary cilia. Understanding which of these processes are altered and how these disruptions contribute to microcephaly pathogenesis is a central unresolved question. In this review, we revisit the different models that have been proposed to explain how centrosome dysfunction impairs cortical development. We review the evidence supporting a unified model in which centrosome defects reduce cell proliferation in the developing cortex by prolonging mitosis and activating a mitotic surveillance pathway. Finally, we also extend our discussion to centrosome-independent microcephaly mutations, such as those involved in DNA replication and repair.

中文翻译:

时间至关重要:原发性小头畸形的分子机制

原发性小头畸形是一种大脑生长障碍,其特征是大脑体积严重缩小和大脑皮层变薄。许多原发性小头畸形突变发生在编码中心体蛋白的基因中,突出了中心体在皮质发育中的重要作用。中心体是参与多个过程的微管组织中心,包括控制极性、催化有丝分裂中的纺锤体组装和构建初级纤毛。了解这些过程中的哪些被改变以及这些破坏如何导致小头畸形发病机制是一个未解决的核心问题。在这篇综述中,我们重新审视了为解释中心体功能障碍如何损害皮质发育而提出的不同模型。我们回顾了支持统一模型的证据,其中中心体缺陷通过延长有丝分裂和激活有丝分裂监视途径来减少发育中皮层的细胞增殖。最后,我们还将讨论扩展到与中心体无关的小头畸形突变,例如那些参与 DNA 复制和修复的突变。
更新日期:2021-12-04
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