State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
Univ. Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Grenoble, F-38000, France.
Development. 2021 Dec 1;148(23). doi: 10.1242/dev.199805. Epub 2021 Dec 7.
Defects in the structure or motility of cilia and flagella may lead to severe diseases such as primary ciliary dyskinesia (PCD), a multisystemic disorder with heterogeneous manifestations affecting primarily respiratory and reproductive functions. We report that CFAP61 is a conserved component of the calmodulin- and radial spoke-associated complex (CSC) of cilia. We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype. We generated Cfap61 knockout mice that recapitulate the infertility phenotype of the human CFAP61 mutation, but without other symptoms usually observed in PCD. We find that CFAP61 interacts with the CSC, radial spoke stalk and head. During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired. As spermiogenesis progresses, the axoneme in Cfap61-/- cells becomes unstable and scatters, and the distribution of intraflagellar transport proteins is disrupted. This study reveals an organ-specific mechanism of axoneme stabilization that is related to male infertility.
纤毛和鞭毛的结构或运动缺陷可能导致严重疾病，如原发性纤毛运动障碍（PCD），这是一种多系统疾病，表现多样，主要影响呼吸和生殖功能。我们报告 CFAP61 是纤毛中钙调蛋白和辐射辐条相关复合物（CSC）的保守成分。我们发现 CFAP61 的剪接变异体 c.143+5G>A 导致人类外显子跳跃/内含子保留，从而诱导鞭毛的多种形态异常（MMAF）表型。我们生成了 Cfap61 敲除小鼠，该小鼠重现了人类 CFAP61 突变的不育表型，但没有 PCD 中通常观察到的其他症状。我们发现 CFAP61 与 CSC、辐射辐条茎和头部相互作用。在 Cfap61-/-精母细胞发育的早期阶段，辐射辐条成分的组装受到损害。随着精子发生的进展，Cfap61-/-细胞中的轴丝变得不稳定并分散，并且内鞭毛运输蛋白的分布被破坏。这项研究揭示了与男性不育相关的轴丝稳定的特定器官机制。
