Genetic evidence for Amh modulation of gonadotropin actions to control gonadal homeostasis and gametogenesis in zebrafish and its noncanonical signalling through Bmpr2a receptor

Abstract

Anti-Müllerian hormone (AMH/Amh) plays an important role in gonadal function. Amh deficiency caused severe gonadal dysgenesis and dysfunction in zebrafish with gonadal hypertrophy in both sexes. However, its action mechanism remains unknown. Intriguingly, the Amh cognate type II receptor (Amhr2) is missing in the zebrafish genome, in sharp contrast to other species. Using a series of zebrafish mutants (amh, fshb, fshr and lhcgr), we provided unequivocal evidence for Amh actions via modulating gonadotropin signaling on both germ cell proliferation and differentiation. The gonadal hypertrophy in amh mutants was abolished in the absence of FSH receptor (Fshr) in females or Fshr/LH receptor (Lhcgr) in males. Furthermore, we demonstrated that knockout of bone morphogenetic protein (BMP) type II receptor A (bmpr2a), but not bmpr2b, phenocopied all phenotypes of amh mutant in both sexes, including gonadal hypertrophy, hyper-proliferation of germ cells, retarded gametogenesis and reduced fshb expression. In summary, the present study provided comprehensive genetic evidence for an intimate interaction of gonadotropin and Amh pathways in gonadal homeostasis and gametogenesis and for Bmpr2a as the possible missing link for Amh signaling in zebrafish.