Microcephaly models in the developing zebrafish retinal neuroepithelium point to an underlying defect in metaphase progression.
Microcephaly models in the developing zebrafish retinal neuroepithelium point to an underlying defect in metaphase progression.
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DOI：
10.1098/rsob.130065
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发表时间：
2013-10-23
期刊：
影响因子：
5.8
通讯作者：
Harris WA
中科院分区：
文献类型：
--
作者：
Novorol C;Burkhardt J;Wood KJ;Iqbal A;Roque C;Coutts N;Almeida AD;He J;Wilkinson CJ;Harris WA
常染色体隐性遗传性原发性小头畸形（MCPH）是一种先天性疾病，其特征是大脑尺寸显着缩小和智力低下。目前已知有九个基因与这种情况有关，所有这些基因都编码中心体或纺锤体极蛋白。 MCPH 与胎儿发育过程中神经祖细胞增殖减少有关。然而，增殖缺陷背后的细胞机制尚未完全了解。斑马鱼视网膜神经上皮为研究这个问题提供了一个理想的系统。三个已知 MCPH 基因（stil、aspm 和 wdr62）和第四个中心体基因 odf2（与几种 MCPH 蛋白相关）的突变或吗啉介导的敲除，会导致头部和眼睛尺寸显着减小。影像学研究显示，在所有情况下，有丝分裂中增殖细胞的比例都急剧上升，延时显微镜显示进展到中期的失败。所有 MCPH 模型中细胞凋亡也有所增加，但这似乎是继发于有丝分裂缺陷，因为我们经常看到有丝分裂停滞的细胞消失，并且敲低 p53 细胞凋亡并不能挽救整个视网膜或克隆中的有丝分裂表型。
Autosomal recessive primary microcephaly (MCPH) is a congenital disorder characterized by significantly reduced brain size and mental retardation. Nine genes are currently known to be associated with the condition, all of which encode centrosomal or spindle pole proteins. MCPH is associated with a reduction in proliferation of neural progenitors during fetal development. The cellular mechanisms underlying the proliferation defect, however, are not fully understood. The zebrafish retinal neuroepithelium provides an ideal system to investigate this question. Mutant or morpholino-mediated knockdown of three known MCPH genes (stil, aspm and wdr62) and a fourth centrosomal gene, odf2, which is linked to several MCPH proteins, results in a marked reduction in head and eye size. Imaging studies reveal a dramatic rise in the fraction of proliferating cells in mitosis in all cases, and time-lapse microscopy points to a failure of progression through prometaphase. There was also increased apoptosis in all the MCPH models but this appears to be secondary to the mitotic defect as we frequently saw mitotically arrested cells disappear, and knocking down p53 apoptosis did not rescue the mitotic phenotype, either in whole retinas or clones.
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