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. Highlights xxxx
Gopal Kushawah, Stephanie H. Nowotarski, Carmichael Carrie et al.· bioRxiv· 0 citations
Cth1 is a highly deposited maternal mRNA that undergoes rapid decay 3’UTR of Cth1 drives its spatio-temporal dynamics, establishing Cth1 as a key component of the maternal program and providing the first direct evidence that spatio-temporally regulated mRNA decay, outside the germline, contributes to early vertebrate development.
Gopal Kushawah, Victor Daniel Aldas Bulos, Danielson Baia Amaral et al.· bioRxiv· 1 citation
Maternal mRNA decay is essential for the Maternal-to-Zygotic Transition (MZT), yet its impact on spatial regulation has remained largely unexplored. We identify Cth1 as the first maternally encoded RNA-decay factor regulated in a spatiotemporal manner outside the germline in zebrafish, driven by conserved 3′UTR cis-elements. RfxCas13d-mediated depletion of maternal cth1 revealed early developmental defects that could not be assessed with SpyCas9 mutants due to infertility from impaired gametogenesis. Mechanistically, Cth1 acts independently of zygotic genome activation, recognizing AU-rich motifs in maternal 3′UTRs to promote deadenylation and decay in a spatio-temporal manner; deletion of these motifs or depletion of Cth1 stabilizes both reporter and endogenous transcripts. These findings establish Cth1 as a key component of the maternal program and provide the first direct evidence that spatio-temporally regulated mRNA decay, outside the germline, contributes to early vertebrate development. Highlights Cth1 is a highly deposited maternal mRNA that undergoes rapid decay 3’UTR of Cth1 drives its spatio-temporal dynamics. Cth1 is essential for gametogenesis and early embryonic development. CTH1 recognizes AU-rich elements in target 3′UTRs to trigger decay.
Gopal Kushawah, Victor Daniel Aldas Bulos, Danielson Baia Amaral et al.· bioRxiv· 1 citation· ⚡1
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