G protein-coupled estrogen receptor is not required for sex determination or ovary function in zebrafish

Abstract

Estrogens regulate vertebrate development and function through binding to nuclear estrogen receptors alpha and beta (ERa, ERb) and the G protein-coupled estrogen receptor (GPER). Studies in mutant animal models demonstrated that ERa and ERb are required for normal ovary development and function. However, the degree to which GPER signaling contributes to ovary development and function is less well understood. Previous studies using cultured fish oocytes found that estradiol inhibits oocyte maturation in a GPER-dependent manner, but whether GPER regulates oocyte maturation in vivo is not known. To test the hypothesis that GPER regulates oocyte maturation in vivo, we assayed ovary development and function in gper mutant zebrafish. We found that homozygous mutant gper embryos developed into male and female adults with normal sex ratios and fertility. Adult mutant fish exhibited normal secondary sex characteristics and fertility. Additionally, mutant ovaries were histologically normal. We observed no differences in the number of immature versus mature oocytes in mutant versus wild-type ovaries from both young and aged adults.Furthermore, expression of genes associated with sex determination and ovary function were normal in gper mutant ovaries compared to wild type. Our findings suggest that GPER is not required for sex determination, ovary development or fertility in zebrafish.

Shedding new light on early sex determination in zebrafish

“…Recent studies have pointed to PSD in zebrafish in which multiple genes along with the influences of primordial germ cells dictate the sexual fate of zebrafish (Von Hofsten and Olsson 2005;Anderson et al 2012;Liew et al 2012;Liew 2013;Nagabhushana and Mishra 2016;Chen et al 2017;Yang et al 2017). Genes contributing to sex determination and gonadal differentiation are distributed throughout the genome, with the combination and interaction of this network of alleles establishing the sex of the individual (Bulmer and Bull 1982;Liew et al 2012;Wilson et al 2014;Crowder et al 2018b).…”

“…Several genes, including aromatase, cyp19a1a and forkhead box L2a (foxl2a) promote ovary differentiation and development (Siegfried and Nüsslein-Volhard 2008;Clelland and Peng 2009;Dranow et al 2016;Chen et al 2017). In addition, sex differentiation can be biased in favour of fully functioning and fertile females when juvenile zebrafish are exposed to exogenous oestrogens (Örn et al 2006;Schulz et al 2007;Crowder et al 2018b). On the other hand, male sex determination is initiated by expression of sex-determining genes that activate downstream factors essential for testis development and spermatogenesis, anti-Mullerian hormones (amh); dmrt1 and sry-related HMGbox 9 (sox9) (Rodríguez-Marí et al 2005;Schulz et al 2007;Herpin and Schartl 2015;Jie and Jian-fang 2015;Lin et al 2017a).…”

Comparison of Sex Determination in Vertebrates (Nonmammals)

“…In the Chinese tongue sole (Cynoglossus semilaevis), genetic ZZ females may change into pseudomales, thereby increasing aquaculture costs because of the lower growth rate of the males than that of the females. A new locus was identified to regulate sex reversal interactively with the SNPCyn_Z_6676874; the linkage between these two loci and the absence of W sperm for pseudomales clearly elucidate the genetic architecture of sex reversal in the tongue sole [15]. Sexual determination in zebrafish is unique in that laboratory strains lack a sex chromosome, and no sex determining gene has been identified.…”

“…Gnrhs, gonadotropin-releasing hormones; Gths, gonadotropins; and Gthrs, gonadotropin receptors (adopted from Wu and Chang [16]). factors regulating c yp19a1 a expression are strong candidates for the trigger that initiates gonadal sex change; c yp19a1 a promoter regions contain binding motifs for numerous factors that potentially regulate its expression [15].…”

G protein-coupled estrogen receptor, a potential therapeutic target of asthma probed by Chinese herb

“…As a newly found membrane receptor of ER, GPER is responsible for the rapid nongenomic actions of ER. Additionally, the effects of GPER on secondary sex characteristics and its distribution in tissues are far less than that of ER nuclear receptors, 11 which makes it possible to avoid many ER‐related adverse reactions. More importantly, this study highlights GPER as a crucial regulator of the immune process upstream of Th2 inflammation.…”