Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia
Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia
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DOI：
10.1242/dmm.038489
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发表时间：
2019-08-01
影响因子：
4.3
通讯作者：
Tocchini-Valentini, Glauco P.
中科院分区：
文献类型：
--
作者：
Chiani, Francesco;Orsini, Tiziana;Tocchini-Valentini, Glauco P.
原发性纤毛运动障碍（PCD）是一种影响运动纤毛正常结构和功能的遗传异质性疾病，表型表现为慢性呼吸道感染、偏侧性缺陷和不育。编码纤毛轴丝不同成分的基因的常染色体隐性突变与人类和模型生物体中的 PCD 相关。 CCDC151 基因编码卷曲螺旋轴丝蛋白，确保外动力蛋白臂 (ODA) 复合物正确附着到微管上。需要正确排列动力蛋白臂复合体来提供纤毛跳动所需的适当机械力。人类 CCDC151 的功能丧失突变会导致 PCD 疾病，伴有呼吸窘迫和左右身体不对称缺陷。在携带 Ccdc151(snbl) 功能丧失突变（Snowball 突变体）的小鼠中，观察到左右身体不对称并伴有心脏缺陷。在这里，我们证明，通过小鼠定向基因删除导致 Ccdc151 基因功能丧失会导致围产期死亡和先天性脑积水。微计算机断层扫描 (microCT) X 射线成像显示 Ccdc151-β-半乳糖苷酶报告基因在全脑中的表达以及组织学分析表明 Ccdc151 在脑室脑系统内壁的室管膜细胞中表达，进一步证实了 Ccdc151 功能障碍在脑积水发展中的作用。通过 microCT 体积成像分析 Ccdc151 敲除动物的脑积水特征，我们观察到 Sylvius 导水管的连续性，表明 Ccdc151 敲除动物脑积水的连通性。在 Ccdc151 缺失的动物中也观察到左右不对称的先天性缺陷和男性不育。成年动物的 Ccdc151 基因缺失会导致精子数量异常和精子活力缺陷。本文有与该论文共同第一作者的相关第一人称采访。
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting normal structure and function of motile cilia, phenotypically manifested as chronic respiratory infections, laterality defects and infertility. Autosomal recessive mutations in genes encoding for different components of the ciliary axoneme have been associated with PCD in humans and in model organisms. The CCDC151 gene encodes for a coiled-coil axonemal protein that ensures correct attachment of outer dynein arm (ODA) complexes to microtubules. A correct arrangement of dynein arm complexes is required to provide the proper mechanical force necessary for cilia beat. Loss-of-function mutations in CCDC151 in humans leads to PCD disease with respiratory distress and defective left-right body asymmetry. In mice with the Ccdc151(snbl) loss-of-function mutation (Snowball mutant), left-right body asymmetry with heart defects have been observed. Here, we demonstrate that loss of Ccdc151 gene function via targeted gene deletion in mice leads to perinatal lethality and congenital hydrocephalus. Microcomputed tomography (microCT) X-ray imaging of Ccdc151-beta-galactosidase reporter expression in whole-mount brain and histological analysis show that Ccdc151 is expressed in ependymal cells lining the ventricular brain system, further confirming the role of Ccdc151 dysfunction in hydrocephalus development. Analyzing the features of hydrocephalus in the Ccdc151-knockout animals by microCT volumetric imaging, we observe continuity of the aqueduct of Sylvius, indicating the communicating nature of hydrocephalus in the Ccdc151-knockout animals. Congenital defects in left-right asymmetry and male infertility have been also observed in Ccdc151-null animals. Ccdc151 gene deletion in adult animals results in abnormal sperm counts and defective sperm motility.This article has an associated First Person interview with the joint first authors of the paper.