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- Title
Genetic analysis of activin/inhibin β subunits in zebrafish development and reproduction.
- Authors
Zhao, Cheng; Zhai, Yue; Geng, Ruijing; Wu, Kun; Song, Weiyi; Ai, Nana; Ge, Wei
- Abstract
Activin and inhibin are both dimeric proteins sharing the same β subunits that belong to the TGF-β superfamily. They are well known for stimulating and inhibiting pituitary FSH secretion, respectively, in mammals. In addition, activin also acts as a mesoderm-inducing factor in frogs. However, their functions in development and reproduction of other species are poorly defined. In this study, we disrupted all three activin/inhibin β subunits (βAa, inhbaa; βAb, inhbab; and βB, inhbb) in zebrafish using CRISPR/Cas9. The loss of βAa/b but not βB led to a high mortality rate in the post-hatching stage. Surprisingly, the expression of fshb but not lhb in the pituitary increased in the female βA mutant together with aromatase (cyp19a1a) in the ovary. The single mutant of βAa/b showed normal folliculogenesis in young females; however, their double mutant (inhbaa-/-;inhbab-/-) showed delayed follicle activation, granulosa cell hypertrophy, stromal cell accumulation and tissue fibrosis. The ovary of inhbaa-/- deteriorated progressively after 180 dpf with reduced fecundity and the folliculogenesis ceased completely around 540 dpf. In addition, tumor- or cyst-like tissues started to appear in the inhbaa-/- ovary after about one year. In contrast to females, activin βAa/b mutant males showed normal spermatogenesis and fertility. As for activin βB subunit, the inhbb-/- mutant exhibited normal folliculogenesis, spermatogenesis and fertility in both sexes; however, the fecundity of mutant females decreased dramatically at 270 dpf with accumulation of early follicles. In summary, the activin-inhibin system plays an indispensable role in fish reproduction, in particular folliculogenesis and ovarian homeostasis. Author summary: Activin and inhibin are important growth factors that play essential roles in animal development and reproduction. Activin and inhibin share the same β subunits, but they are antagonistic in function. Using gene editing technology, we studied the functional roles and importance of all three β subunits (βAs: inhbaa and inhbab; βB: inhbb) in zebrafish development and reproduction. Our results showed that the loss of all three subunits resulted in early death in zebrafish larvae, indicating functional importance of these molecules in development. Further analysis demonstrated essential roles of the β subunits especially βΑs (inhbaa and inhbab) in controlling female follicle development in the ovary. The loss of βΑs especially inhbaa showed delayed follicle activation and ovarian fibrosis. Without inhbaa gene, the ovary deteriorated progressively after 6 months and the formation of eggs stopped completely after 18 months. In summary, the present study provided comprehensive evidence for the relative importance of each β subunit in zebrafish reproduction.
- Subjects
INHIBIN; ANIMAL reproduction; ACTIVIN; BRACHYDANIO; ANIMAL development; REPRODUCTION; MESODERM; SPERMATOGENESIS
- Publication
PLoS Genetics, 2022, Vol 18, Issue 12, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010523