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Follicle-stimulating hormone (FSH) is a gonadotropin released from the pituitary essential for the regulation of folliculogenesis in vertebrates. Unlike mammals, the regulatory mechanism of FSH is unknown in teleosts because gonadotropin-releasing hormone (GnRH) was proven to be dispensable for FSH function. Here, we aimed to identify the FSH-releasing hormone (FSH-RH) by using a model teleost, medaka. We found that knockout of either cholecystokinin receptor,cckbr1, which is highly expressed in the FSH cells, or its ligand cholecystokinin (ccka/cckb), which is expressed in the pituitary projecting neurons, drastically reduced thefshbmRNA expression in the pituitary, resulting in infertility. Also,in vitroexperiments clearly demonstrated that cholecystokinin peptide increases [Ca2+]i of FSH cells andfshbexpression. We hypothesize that this system constitutes the long-missing FSH-RH in teleosts.

The preoptic area (POA) is one of the most evolutionarily conserved regions of the vertebrate brain and contains subsets of neuropeptide-expressing neurons. Here we found in the teleost medaka that two neuropeptides belonging to the secretin family, pituitary adenylate cyclase-activating polypeptide (Pacap) and vasoactive intestinal peptide (Vip), exhibit opposite patterns of sexually dimorphic expression in the same population of POA neurons that project to the anterior pituitary: Pacap is male-biased, whereas Vip is female-biased. Estrogen secreted by the ovary in adulthood was found to attenuate Pacap expression and, conversely, stimulate Vip expression in the female POA, thereby establishing and maintaining their opposite sexual dimorphism. Pituitary organ culture experiments demonstrated that both Pacap and Vip can markedly alter the expression of various anterior pituitary hormones. Collectively, these findings show that males and females use alternative preoptic neuropeptides to regulate anterior pituitary hormones as a result of their different estrogen milieu., Junpei Yamashita et al. use a medaka model to evaluate how neurons in the preoptic area that express the neuropeptides, PACAP and VIP, regulate pituitary hormones. Their results suggest that estrogen helps maintain sex-dependent activity of these neurons, leading to sexually dimorphic pituitary hormone production.

Serotonin is a biogenic monoamine conserved across phyla that is implicated in diverse physiological and behavioural functions. On examining the expression of the rate-limiting enzymes in serotonin synthesis, tryptophan hydroxylases (TPHs), in the teleost medaka ( Oryzias latipes ), we found that males have much higher levels of tph1 expression as compared with females. This robust sexual dimorphism was found to probably result from the direct stimulation of tph1 transcription by androgen/androgen receptor binding to canonical bipartite androgen-responsive elements in its proximal promoter region. Our results further revealed that tph1 expression occurs exclusively in pro-opiomelanocortin ( pomc )-expressing cells and that the resulting serotonin and its derivative melatonin inhibit the expression of the pituitary hormone genes, fshb , sl and tshb . This suggests that serotonin and/or melatonin synthesized in pomc -expressing cells act in a paracrine manner to suppress pituitary hormone levels. Consistent with these findings and the male-biased expression of tph1 , the expression levels of fshb , sl and tshb were all higher in females than in males. Taken together, the male bias in tph1 expression and consequent serotonin/melatonin production presumably contribute to sex differences in the expression of pituitary hormones and ultimately in the physiological functions mediated by them.

Male and female animals display innate sex-specific mating behaviors. In teleost fish, altering the adult sex steroid milieu can effectively reverse sex-typical mating behaviors, suggesting remarkable sexual lability of their brains as adults. In the teleost medaka, neuropeptide B (NPB) is expressed female-specifically in the brain nuclei implicated in mating behavior. Here, we demonstrate that NPB is a direct mediator of estrogen action on female mating behavior, acting in a female-specific but reversible manner. Analysis of regulatory mechanisms revealed that the female-specific expression of NPB is dependent on direct transcriptional activation by estrogen via an estrogen-responsive element and is reversed in response to changes in the adult sex steroid milieu. Behavioral studies of NPB knockouts revealed that female-specific NBP mediates female receptivity to male courtship. The female-specific NPB signaling identified herein is presumably a critical element of the neural circuitry underlying sexual dimorphism and lability of mating behaviors in teleosts.

Male and female animals typically display innate sex-specific mating behaviors, which, in vertebrates, are highly dependent on sex steroid signaling. While estradiol-17β (E2) signaling through estrogen receptor 2 (ESR2) serves to defeminize male mating behavior in rodents, the available evidence suggests that E2 signaling is not required in teleosts for either male or female mating behavior. Here, we report that female medaka deficient for Esr2b, a teleost ortholog of ESR2, are not receptive to males but rather court females, despite retaining normal ovarian function with an unaltered sex steroid milieu. Thus, contrary to both prevailing views in rodents and teleosts, E2/Esr2b signaling in the brain plays a decisive role in feminization and demasculinization of female mating behavior and sexual preference in medaka. Further behavioral testing showed that mutual antagonism between E2/Esr2b signaling and androgen receptor-mediated androgen signaling in adulthood induces and actively maintains sex-typical mating behaviors and preference. Our results also revealed that the female-biased sexual dimorphism in esr2b expression in the telencephalic and preoptic nuclei implicated in mating behavior can be reversed between males and females by altering the sex steroid milieu in adulthood, likely via mechanisms involving direct E2-induced transcriptional activation. In addition, Npba, a neuropeptide mediating female sexual receptivity, was found to act downstream of E2/Esr2b signaling in these brain nuclei. Collectively, these functional and regulatory mechanisms of E2/Esr2b signaling presumably underpin the neural mechanism for induction, maintenance, and reversal of sex-typical mating behaviors and sexual preference in teleosts, at least in medaka.

Vertebrate brains are sexually differentiated, giving rise to differences in various physiological and behavioral phenotypes between the sexes. In developing mammals and birds, the neural substrate underlying sex-dependent physiology and behavior undergoes an irreversible process of sexual differentiation due to the effects of perinatal gonadal steroids and sex chromosome complement. The differentiated neural substrate is then activated in the adult by the sex-specific steroid milieu to facilitate the expression of sex-typical phenotypes. However, this well-established concept does not hold for teleost fish, whose sexual phenotypes (behavioral or otherwise) are highly labile throughout life and can be reversed even in adulthood. Indeed, the available evidence suggests that, in teleosts, neither gonadal steroids early in development nor the sex chromosome complement contribute much to brain sexual differentiation; instead, steroids in adulthood serve to both differentiate the neural substrate and activate it to elicit sex-typical phenotypes in a transient and reversible manner. Evidence further suggests that marked sexual dimorphisms and adult steroid-dependent lability in the neural expression of sex steroid receptors constitute the primary molecular basis for sexual differentiation and lability of the teleost brain. The consequent sexually dimorphic but reversible steroid sensitivity in response to the adult steroid milieu may enable the teleost brain to maintain lifelong sexual lability and to undergo phenotypic sex reversal.