PDF(Pubmed)
Abstract：
Odad3 gene loss-of-function mutation leads to Primary Ciliary Dyskinesia (PCD), a disease caused by motile cilia dysfunction. Previously, we demonstrated that knockout of the Odad3 gene in mice replicates several features of PCD, such as hydrocephalus, defects in left-right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract. The majority of Odad3 knockout animals die before sexual maturation due to severe hydrocephalus and failure to thrive, which precludes fertility studies. Here, we performed the expression analysis of the Odad3 gene during gonad development and in adult testes. We showed that Odad3 starts its expression during the first wave of spermatogenesis, specifically at the meiotic stage, and that its expression is restricted to the germ cells in the adult testes, suggesting that Odad3 plays a role in spermatozoa formation. Subsequently, we conditionally deleted the Odad3 gene in adult males and demonstrated that even partial ablation of the Odad3 gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice. The analysis of the seminiferous tubules in Odad3-deficient mice revealed defects in spermatogenesis with accumulation of seminiferous tubules at the spermiogenesis and spermiation phases. Furthermore, analysis of fertility in heterozygous Odad3+/- knockout mice revealed a reduction in sperm count and motility as well as abnormal sperm morphology. Additionally, Odad3+/- males exhibited a shorter fertile lifespan. Overall, these results suggest the important role of Odad3 and Odad3 gene dosage in male fertility. These findings may have an impact on the genetic and fertility counseling practice of PCD patients carrying Odad3 loss-of-function mutations.
摘要：
Odad3基因功能缺失突变导致原发性纤毛运动障碍（PCD），由活动纤毛功能障碍引起的疾病。以前,我们证明了小鼠中Odad3基因的敲除复制了PCD的几个特征，比如脑积水，左右身体对称性的缺陷，和男性不育,生殖道中完全没有精子。大多数Odad3基因敲除的动物在性成熟前由于严重的脑积水和无法茁壮成长而死亡，这就排除了生育研究。这里,我们在性腺发育和成年睾丸中进行了Odad3基因的表达分析。我们表明Odad3在第一波精子发生过程中开始表达，特别是在减数分裂阶段，它的表达仅限于成年睾丸的生殖细胞，表明Odad3在精子形成中起作用。随后，我们有条件地删除了成年男性的Odad3基因,并证明即使部分切除Odad3基因,也会导致小鼠精子鞭毛(MMAF)形态异常的弱精子症.对Odad3缺陷小鼠的精细管的分析显示，精子发生缺陷，精细管在精子发生和精子发生阶段积累。此外，对杂合子Odad3+/-基因敲除小鼠的生育力分析显示精子数量和运动性减少以及精子形态异常。此外,Odad3/-雄性的生育能力较短。总的来说,这些结果表明Odad3和Odad3基因剂量在男性生育力中的重要作用。这些发现可能对携带Odad3功能丧失突变的PCD患者的遗传和生育咨询实践产生影响。
