Photoperiod regulates gonadotrope cell division in medaka via melatonin, Tsh and folliculostellate cells

In vertebrates, pituitary gonadotropins (follicle-stimulating and luteinizing hormones: FSH and LH) regulate gonadal development and maturation, therefore playing an essential role in reproduction. The seasonal regulation of gonadotropins has been widely studied in mammals and birds, and in these taxa thyroid-stimulating hormone (TSH) was found to play a critical role. By contrast, the seasonal regulation of gonadotropins remains unclear in teleost fish. In addition, the seasonal regulation of gonadotrope (gonadotropin-producing cell) proliferation has not been elucidated in any vertebrate group. Using the teleost fish medaka as a model, we show for the first time that long photoperiod enables reproduction by stimulating gonadotropin mRNA synthesis and gonadotrope cell proliferation. In female medaka, this proliferation is achieved by gonadotrope mitosis. We then demonstrate that in female medaka, photoperiod stimulates gonadotropin mRNA production and mitosis via an indirect intra-pituitary pathway, involving pituitary Tsh cells. We show that non-endocrine folliculostellate cells in the pituitary mediate the Tsh signal regulating gonadotrope activity and proliferation, as they are the only pituitary cells to express Tsh receptors and send projections to gonadotropes. Finally, we show that melatonin suppresses pituitary tshba expression in fish exposed to long photoperiod, suggesting that short photoperiod inhibits gonadotropin synthesis via melatonin in both fish and mammals. This study therefore demonstrates that in fish, photoperiod regulates gonadotrope cell activity and mitosis via a melatonin-Tsh pathway. It also reveals the existence of a novel intra-pituitary pathway for seasonal regulation of gonadotropes, involving folliculostellate cells, which we propose might also exist in other vertebrates. SIGNIFICANCEIn seasonally breeding mammals and birds, the production of the hormones that regulate reproduction (gonadotropins) by gonadotropes is controlled by the pituitary thyroid-stimulating hormone (TSH) through an indirect pathway via the brain. However, in fish, how seasonal environmental signals influence gonadotropins remains unclear. Here, we show that in a long day seasonally breeding fish, medaka, photoperiod not only regulates the activity (hormone production) of the gonadotropes but also their proliferation. We also reveal a novel intra-pituitary pathway that regulates gonadotrope cell activity and number. This pathway involves melatonin, Tsh, and folliculostellate cells. Interestingly, as all these components are also found in the mammalian pituitary, this study suggests the existence of an alternative regulatory mechanism of seasonal gonadotropin production across vertebrates.