Cth1 is essential for gametogenesis and fertility in zebrafish

Abstract

Infertility frequently arises from defects in germ cells and early embryonic transition. Successful fertilization depends on the developmental competence and molecular integrity of mature gametes from both parents, which are established through tightly coordinated programs of RNA regulation, metabolism, and genome maintenance. In our previous work, we identified Cth1 as a maternally regulated RNA decay factor essential for early embryonic development, acting through spatiotemporal control of maternal transcript clearance. Interestingly, Cth1 loss of function in adults also resulted in infertility, suggesting an additional and unexplored role during gametogenesis. Here, we extend these findings by defining the gametogenic function of Cth1 in zebrafish. Through detailed phenotypic, cytological and molecular characterization of Cth1 loss of function mutants, we show that Cth1 is highly enriched in germ cells and early embryos and is spatio-temporally localized across oogenesis and early development. Loss of Cth1 causes severe defects in early oogenesis and spermatogenesis, resulting in complete infertility in males and females. Mutant germ cells display transcriptomic changes consistent with metabolic and translational dysregulation, increased DNA damage, and striking abnormalities in gamete morphology. Together, these findings identify Cth1 as essential for gamete quality and fertility. Our study suggests a link between RNA decay mediated regulation of metabolism and genome integrity during germ cell development and reveals disruption of post-transcriptional control as a potential mechanism underlying infertility.