It Takes Two Gonadotropins to Tango in Zebrafish But With a Mixed Tune.

Abstract

In vertebrates, reproduction is under the tight control of a third order neuroendocrine loop. This 3-tiered axis, consisting of the hypothalamus, anterior pituitary gland, and gonads, is known as the hypothalamus-pituitary-gonadal axis. At the center of this hypothalamus-pituitarygonadal axis, the anterior pituitary gland secretes 2 gonadotropins, namely FSH and LH. Both FSH and LH are heterodimeric glycoproteins, sharing a common -subunit and a hormone-specific -subunit (FSH or LH ). FSH acts via the FSH receptor (FSHR), a G protein-coupled receptor expressed exclusively on the granulosa cells in the ovary and Sertoli cells in the testis, to stimulate folliculogenesis in female and spermatogenesis in male. LH, on the other hand, works through the LH receptor (also known as luteinizing hormone/choriogonadotropin receptor: LHCGR), another GPCR expressed on the theca cells in the ovary and Leydig cells in the testis, to promote steroidogenesis (1). This dogma is described in endocrinology textbooks, and it is well supported by genetic studies using the mouse model and by genetic mutations occurring in human patients. For example, knockout of the FSH gene (Fshb) or the FSHR (Fshr) gene leads to the folliculogenesis arrest at the preantral stage, resulting in infertility in female mice. The Fshb and Fshr null male mice, however, are fertile, albeit with smaller testes and reduced fecundity (2–4, also see Figure 1). In comparison, knockout of either the Lh (Lhb) or the Lhcgr (Lhcgr) gene leads to infertility in both male and female in mice (5–7, also see Figure 1). In this issue of Endocrinology, Ge and coworkers (8) at the University of Macau and The Chinese University of Hong Kong reported some new and interesting results that shed new light on the functions of Fshr and Lhcgr in zebrafish (see Figure 1). These authors showed that 1) knockout of the zebrafish fshr gene had genderspecific effects. Although the fshr / male fish were fertile (albeit with delayed spermatogenesis), knockout of the fshr gene in female led to a complete failure of follicle activation in the ovary, and all the follicles were arrested at early primary growth stage. These phenotypes are similar to what has been reported in mammals, suggesting that Fshr-mediated signaling plays a conserved role in controlling folliculogenesis in mammals and fish. 2) Genetic ablation of Lhcgr had no effect on folliculogenesis in the female or spermatogenesis in the male. Both male and female lhcgr / fish were fertile (8). This agrees well with another genetic study in zebrafish (9). Based on these findings, one may conclude that the Lhcgr-mediated signaling is dispensable in zebrafish. However, Ge and coworkers (8) discovered that double knockout of the 2 receptors resulted in complete infertility in both male and female fish, suggesting that Lhcgr-mediated signaling is functional in the absence of Fhsr-mediated signaling. In a related study published earlier this year, Ge and coworkers explored the functions of Fsh and Lh proteins by genetic disruption of the zebrafish FSH (fshb) and/or LH (lhb) genes. They showed that both the male and female fshb / fish were fertile (although with delayed spermatogenesis or folliculogenesis) (10). Although the lhb / null male fish were fertile, the female fish were infertile. This female infertility is due to a failure in spawning because the lhb / null female fish showed normal ovary growth (10). This result indicates that zebrafish Lh is