Evolution of the Hypothalamic-Pituitary-Gonadal Axis Regulation in Vertebrates Revealed by Knockout Medaka

Abstract

Reproduction is essential for life, but its regulatory mechanism is diverse. The analysis of this diversity should lead us to understand the evolutionary process of the regulation of reproduction. In mammals, the hypothalamic-pituitary-gonadal axis plays an essential role in such regulation, and each component, hypothalamic GnRH, and pituitary gonadotropins, LH, and FSH, is indispensable. However, the common principle of the hypothalamic-pituitary-gonadal axis regulation among vertebrates remains unclear. Here, we used a teleost medaka, which is phylogenetically distant from mammals, and analyzed phenotypes of gene knockouts (KOs) for GnRH, LH, and FSH. We showed that LH release, which we previously showed to be directly triggered by GnRH, is essential for ovulation in females, because KO medaka of GnRH and LH were anovulatory in spite of the full follicular growth and normal gonadosomatic index, and spawning could be induced by a medaka LH receptor agonist. On the other hand, we showed that FSH is necessary for the folliculogenesis, because the follicular growth of FSH KO medaka was halted at the previtellogenic stage, but FSH release does not necessarily require GnRH. By comparing these results with the previous studies in mammals that both GnRH and LH are necessary for folliculogenesis, we propose a hypothesis as follows. During evolution, LH was originally specialized for ovulation, and regulation of folliculogenesis by GnRH-LH (pulsatile release) was newly acquired in mammals, which enabled fine tuning of reproduction through hypothalamus.

Gnrh1-induced responses are indirect in female medaka Fsh cells

“…This observation is consistent with our finding that the responses of Fsh cells to Gnrh1 were weaker than that of Lh cells. In fact, as previously reported, normal folliculogenesis is seen in Gnrh knockout medaka (13). In addition, in mammals only a 50% reduction in plasma FSH is observed in GnRH deficient hpg mouse (30).…”

“…In the infertile natural GnRH mutant ( hpg ) mouse, FSH serum levels are reduced by 50%, while LH levels are non-detectable (30, 31). Likewise, in the teleost medaka ( Oryzias latipes ), Gnrh knockout in females prevented ovulation and reduced expression of lhb , but did not affect fshb expression or follicle development (13). These results suggest that LH cell function is dependent on GnRH stimulation, while adequate FSH synthesis and release may continue in the absence of GnRH.…”

A compromised gsdf signaling leads to gamatogenesis confusion and subfertility in medaka

“…Higher gonada-somatic index (GSI) was observed in gsdfKO females(Kaiqing Sun1#, 2017) and Sissy intersexes associated with elevation of Fsh in pituitary, supporting that the gonad enlargement resulted from Fsh elevation(Kaiqing Sun1#, 2017) (own data unpublished). An increase in GSI has been observed in lhKO medaka(Takahashi et al, 2016), lhKO and lhrKO zebrafish(Chu et al, 2014), in agreement with findings of less Lh secretory cells and only fshr were elevated in Sissy pituitary and gonad respectively, as the result of less Lh but elevated Fsh in Sissy pituitary (own data unpublished). In the gonadotrophin-dependent phase of follicular development, androgen was produced by cyp19b - and lh -positive theca-interstitial cell layer and diffused into the mural granulosa cell layer, which produced E2 with Fsh-sensitive aromatase catalysis.…”

“…Gsdf depletion not only resulted in XY feminization, but also severely restrained oocyte development at previtellogenic stage(Guan, 2017). Similar phenomena have been observed after targeted disruption of follicle-stimulating hormone ( fsh )(Takahashi et al, 2016), fsh receptor ( fshr )(Murozumi et al, 2014) or an anti-Müllerian hormone receptor II ( amhr2 ) hotei mutant leading to female sterility(Morinaga et al, 2007). Fsh, Amh, androgens, and estradiol (E2) are essential in folliculogenesis in most vertebrates, but displays a wide range of effective varieties in spermatogenesis(Huhtaniemi, 2015).…”

Stress-mediated convergence of splicing landscapes in male and female Rock Doves

“…POU class 2 homeobox 1 365 (POU2F1), a transcription factor that regulates transcription of gonadotropin-releasing hormone (GnRH) (Chandran & DeFranco, 1999;Cheng et al, 2002), is alternatively spliced in the male pituitary stress response. GnRH is a primary regulator of the HPG axis (Pohl et al, 1983;Campbell, Dobson & Scaramuzzi, 1998;Takahashi et al, 2016).…”