Lack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors.
Lack of Diaph3 relaxes the spindle checkpoint causing the loss of neural progenitors.
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DOI：
10.1038/ncomms13509
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发表时间：
2016-11-16
影响因子：
16.6
通讯作者：
Tissir F
中科院分区：
文献类型：
--
作者：
Damiani D;Goffinet AM;Alberts A;Tissir F
透明同源蛋白Diaph3（又名mDia2）是肌动蛋白细胞骨架的主要调节因子。由于卵裂沟中肌动蛋白的积累受损，隔膜的缺失一直与细胞分裂失败有关。在这里，我们报告了在细胞分裂之前需要隔膜，以确保染色体的准确分离。膜片基因失活导致皮质祖细胞大量丧失，随后中间祖细胞和神经元耗竭，导致小头畸形。在胚胎脑提取物中，Diaph3与BubR1共同免疫沉淀，BubR1是纺锤体组装检查点（SAC）的关键调节因子。膜片缺陷皮质祖细胞的BubR1水平降低，不能正确激活SAC。因此，尽管不正确的染色体分离，它们绕过有丝分裂阻滞，进入后期，产生非整倍体。我们的数据确定了膈肌是皮质祖细胞的主要守卫，揭示了膈肌形成蛋白的新功能，并为小头畸形的病理生物学提供了新的见解。控制神经祖细胞分裂的分子机制只被部分理解。作者发现，在皮质祖细胞中，膜片3对纺锤体检查点活性至关重要，因为膜片3的缺失会导致祖细胞凋亡，最终导致小鼠小头畸形。
The diaphanous homologue Diaph3 (aka mDia2) is a major regulator of actin cytoskeleton. Loss of Diaph3 has been constantly associated with cytokinesis failure ascribed to impaired accumulation of actin in the cleavage furrow. Here we report that Diaph3 is required before cell fission, to ensure the accurate segregation of chromosomes. Inactivation of the Diaph3 gene causes a massive loss of cortical progenitor cells, with subsequent depletion of intermediate progenitors and neurons, and results in microcephaly. In embryonic brain extracts, Diaph3 co-immunoprecipitates with BubR1, a key regulator of the spindle assembly checkpoint (SAC). Diaph3-deficient cortical progenitors have decreased levels of BubR1 and fail to properly activate the SAC. Hence, they bypass mitotic arrest and embark on anaphase in spite of incorrect chromosome segregation, generating aneuploidy. Our data identify Diaph3 as a major guard of cortical progenitors, unravel novel functions of Diaphanous formins and add insights into the pathobiology of microcephaly. Molecular mechanisms that control the division of neural progenitor cells are only partially understood. Here the authors show that Diaph3 is critical for spindle checkpoint activity in cortical progenitor cells as the loss of Diaph3 leads to apoptosis of progenitor cells and eventually results in microcephaly in mice.