Abstract
The zinc transporter ZIP9 (SLC39A9) was recently characterized as a membrane androgen receptor in various teleost and mammalian cell models. ZIP9 shows the highest expression in ovaries of teleosts, a tissue in which both androgen signaling and zinc dynamics have significant roles. To examine the role of ZIP9 in ovarian physiology, we generated a ZIP9-mutant zebrafish strain using a CRISPR/Cas9 system. zip9-/- females showed significant reductions in fecundity, embryo viability, and growth of their offspring compared to wildtype (WT) fish. Furthermore, a high proportion of zip9-/- eggs failed to undergo normal chorion elevation during activation. In WT eggs, zinc was detected in cortically-localized vesicles which underwent exocytosis upon activation. zip9-/- eggs showed abnormal cortical vesicle development and had a significantly depressed activation-induced zinc release compared to WT eggs. Moreover, pharmacologically sustained elevation of zinc in WT eggs prior to activation resulted in abnormal chorion elevation similar to that observed in zip9-/- eggs. These results indicate that ZIP9 is essential for proper zinc modulation during zebrafish egg activation and presents the first evidence of zinc modulation during egg activation in a non-mammalian species.
Highlights
The zinc transporter SLC39A9 (ZIP9) was found to possess membrane androgen receptor activity[1,2], and is the only zinc transporter known to have hormone receptor activity
We observed that in wildtype meiosis II-arrested eggs, zinc is stored in cortically-localized vesicles that undergo exocytosis upon egg activation. zip9-/- eggs showed a reduced zinc exocytosis response compared to wildtype eggs, which corresponded with abnormal cortical vesicle morphology
We present the first evidence for a role of the zinc transporter/membrane androgen receptor ZIP9 in the reproductive success of a female vertebrate. zip9-mutants show reduced fecundity, egg viability, and reduced larval growth and survival. zip9-/- females produce a high proportion of eggs that undergo abnormal chorion elevation, which coincides with abnormalities in cortical vesicle morphology throughout oogenesis
Summary
The zinc transporter SLC39A9 (ZIP9) was found to possess membrane androgen receptor (mAR) activity[1,2], and is the only zinc transporter known to have hormone receptor activity. ZIP9 has been shown to mediate androgeninduced apoptosis and survival of teleost granulosa/theca (G/T) c ells[1,3], an apoptotic response in prostate and breast cancer c ells[2,4], migration of prostate and bladder cancer c ells[5,6], and tight junction formation in murine Sertoli cells[7] In many of these models, androgen activation of ZIP9 results in elevation of intracellular zinc levels which in turn modulates the downstream physiological response[1,2,3,4]. ZIP9 is primarily expressed in gonadal and brain tissues in Atlantic c roaker[1], which indicates a potential role of this protein in teleost reproductive physiology While both androgens and zinc play vital roles in ovarian physiology, the function of ZIP9 in mediating nonclassical androgen actions and zinc transport within the ovary remains unclear. This work provides the first evidence that zinc modulation occurs during egg activation in a non-mammalian vertebrate model and demonstrates that ZIP9 plays a vital role in the zinc regulatory events that allow for proper egg activation in zebrafish
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