Zebrafish Nedd8 Facilitates Ovarian Development and the Maintenance of Female Secondary Sexual Characteristics Via Suppression of Androgen Receptor Activity

Abstract

Nedd8 is an ubiquitin-like protein that covalently conjugates to target proteins through neddylation. In addition to cullin-RING ligases, neddylation also modifies non-cullin proteins to regulate protein activity, stability, and localization. However, the roles of NEDD8 remain largely unknown in vivo. Here, we found that loss of nedd8 in female zebrafish led to defects in ovarian development, disrupted oocyte maturation and stimulated growth of the breeding tubercles (BTs) on the pectoral fins. However, the loss of one copy of ar can partially rescued the phenotypes displayed by nedd8-null female zebrafish. Further assays indicated that Ar conjugated to Nedd8 and Ar is neddylated at lysine 76 and lysine 558. Moreover, Nedd8 conjugation efficiently suppressed Ar transcriptional activity. Thus, our results not only demonstrated that nedd8 modulates ovarian development and the formation of male secondary sexual characteristics in female zebrafish in vivo, but also indicated that androgen signaling is strictly regulated by nedd8.

Keywords: nedd8, zebrafish, androgen receptor, ovary, testis, neddylation