Ankle2 deficiency-associated microcephaly and spermatogenesis defects in zebrafish are alleviated by heterozygous deletion of vrk1.
Ankle2 deficiency-associated microcephaly and spermatogenesis defects in zebrafish are alleviated by heterozygous deletion of vrk1.
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斑马鱼中 Ankle2 缺陷相关的小头畸形和精子发生缺陷可通过杂合删除 vrk1 得到缓解。
DOI：
10.1016/j.bbrc.2022.07.070
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Hanada T.
中科院分区：
文献类型：
--
作者：
Apridita Sebastian W;Shiraishi H;Shimizu N;Umeda R;Lai S;Ikeuchi M;Morisaki I;Yano S;Yoshimura A;Hanada R;Hanada T.
常染色体隐性遗传性原发性小头畸形（MCPH）是一种罕见的先天性疾病，其特征是出生时脑体积低于平均水平，并与神经发育障碍如生长迟缓和智力残疾有关。ANKLE 2突变已被确定为MCPH（MCPH 16）的原因之一。ANKLE 2是寨卡病毒NS 4a蛋白的靶分子，其干扰ANKLE 2功能，导致严重的小头畸形。ANKLE 2是有丝分裂末期通过自身整合屏障因子（BAF）去磷酸化组织核膜和染色质结构所必需的。然而，ANKLE 2功能丧失导致小头畸形发病的确切机制仍不清楚。在这项研究中，我们产生了Ankle 2缺陷的斑马鱼（ankle 2 −/−），与对照组的兄弟姐妹相比，大脑尺寸显着减小。踝2 −/−脑放射状胶质祖细胞的数量显着减少，表明斑马鱼的踝2缺陷导致神经发生缺陷。此外，踝2 −/−雄性斑马鱼由于精子发生缺陷而表现出不育。值得注意的是，vrk 1吗啉代敲除或vrk 1杂合缺失可克服小头畸形。此外，尽管不育症没有得到解决，但vrk 1杂合缺失部分恢复了踝2 −/−斑马鱼雄性的精子发生。这些结果表明，ANKLE 2和VRK 1相互协调BAF磷酸化，以维持神经发生和精子发生过程中的正常有丝分裂。
Autosomal recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by a below average brain volume at birth and is associated with neurodevelopmental disorders such as growth retardation and intellectual disability. Mutations inANKLE2have been identified as one of the causes of MCPH (MCPH16). ANKLE2 is a target molecule of the Zika virus NS4a protein that interferes with ANKLE2 function, resulting in severe microcephaly. ANKLE2 is essential for organizing the nuclear envelope and chromatin structures during the mitotic-end process via barrier to autointegration factor (BAF) dephosphorylation. However, the precise mechanism by which the loss of ANKLE2 function causes the pathogenesis of microcephaly remains unclear. In this study, we generated Ankle2-deficient zebrafish (ankle2−/−) with a significant reduction in brain size compared with that of their control siblings. Theankle2−/−brain showed a significant decrease in the number of radial glial progenitor cells, suggesting that Ankle2 deficiency in zebrafish causes neurogenesis defects. Furthermore,ankle2−/−male zebrafish showed infertility owing to defects in spermatogenesis. Notably, microcephaly was overcome byvrk1morpholino knockdown orvrk1heterozygous deletion. In addition, spermatogenesis inankle2−/−zebrafish males was partially restored by thevrk1heterozygous deletion, although infertility was not resolved. These results indicate that ANKLE2 and VRK1 coordinate with each other for BAF phosphorylation to maintain normal mitosis during neurogenesis and spermatogenesis.
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10.5
作者：
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