Loss of zinc finger MYND-type containing 10 (zmynd10) affects cilia integrity and axonemal localization of dynein arms, resulting in ciliary dysmotility, polycystic kidney and scoliosis in medaka (Oryzias latipes)
Loss of zinc finger MYND-type containing 10 (zmynd10) affects cilia integrity and axonemal localization of dynein arms, resulting in ciliary dysmotility, polycystic kidney and scoliosis in medaka (Oryzias latipes)
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DOI：
10.1016/j.ydbio.2017.08.016
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发表时间：
2017-10-01
影响因子：
2.7
通讯作者：
Yokoyama, Takahiko
中科院分区：
文献类型：
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作者：
Kobayashi, Daisuke;Asano-Hoshino, Anshin;Yokoyama, Takahiko
纤毛和鞭毛是从细胞表面突出的毛发状细胞器，在运动和感觉感知中起重要作用。纤毛和鞭毛运动缺陷导致原发性纤毛运动障碍（PCD），一种罕见的人类疾病。最近在人类中鉴定出锌指MYND型含10（ZMYND 10）作为PCD相关基因。在这项研究中，我们使用青鳉鱼作为一个模型来描述zmynd 10的精确功能。在青鳉中，zmynd 10仅在具有运动纤毛的细胞中表达。zmynd 10 Morpholino敲低的胚胎表现出与库普弗囊泡（KV）纤毛运动性丧失相关的左右（LR）缺陷。这种不运动性是由外动力蛋白臂的丢失引起的，这是PCD中的特征性超微结构表型。此外，KV纤毛zmynd 10敲除胚胎有肿胀和波浪状的形态。总之，这些结果表明zmynd 10是一种多功能蛋白，在动力蛋白臂的轴丝定位以及纤毛的形成和/或维持中具有独立的作用。zmynd 10的C-末端区域具有对其功能重要的MYND型锌指结构域（zf-MYND）。我们的拯救实验表明，zmynd 10-Delta C截短的蛋白，缺乏zf-MYND，仍然是部分功能，这表明zmynd 10有另一个功能结构域以外的zf-MYND。为了分析发育的后期阶段，我们使用转录激活因子样效应物核酸酶（TALEN）技术产生了zmynd 10敲除突变体。成年突变体表现出精子运动障碍，脊柱侧凸和进行性多囊肾。
Cilia and flagella are hair-like organelles that project from the cell surface and play important roles in motility and sensory perception. Motility defects in cilia and flagella lead to primary ciliary dyskinesia (PCD), a rare human disease. Recently zinc finger MYND-type containing 10 (ZMYND10) was identified in humans as a PCD-associated gene. In this study, we use medaka fish as a model to characterize the precise functions of zmynd10. In medaka, zmynd10 is exclusively expressed in cells with motile cilia. Embryos with zmynd10 Morpholino knockdown exhibited a left-right (LR) defect associated with loss of motility in Kupffer's vesicle (KV) cilia. This immotility was caused by loss of the outer dynein arms, which is a characteristic ultrastructural phenotype in PCD. In addition, KV cilia in zmynd10 knockdown embryos had a swollen and wavy morphology. Together, these results suggest that zmynd10 is a multi-functional protein that has independent roles in axonemal localization of dynein arms and in formation and/or maintenance of cilia. The C-terminal region of zmynd10 has a MYND-type zinc finger domain (zf-MYND) that is important for its function. Our rescue experiment showed that the zmynd10-Delta C truncated protein, which lacks zf-MYND, was still partially functional, suggesting that zmynd10 has another functional domain besides zf-MYND. To analyze the later stages of development, we generated a zmynd10 knockout mutant using transcription activator-like effector nuclease (TALEN) technology. Adult mutants exhibited sperm dysmotility, scoliosis and progressive polycystic kidney.