Roles of Gonadotropin Receptors in Sexual Development of Medaka

Abstract

The gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are secreted from the pituitary and bind to the FSH receptor (FSHR) and LH receptor (LHR) to regulate gonadal development in vertebrates. Previously, using fshr-knockout (KO) medaka (Oryzias latipes), we demonstrated that FSH regulates ovarian development by elevating estrogen levels. However, the lhr-KO phenotype in medaka is poorly characterized. Here, we generated lhr-KO medaka using the transcription activator-like effector nuclease (TALEN) technique. We analyzed its phenotype and that of fshr-KO, lhr;fshr double-heterozygotes (double-hetero), and double-KO fish. All genetically male medaka displayed normal testes and were fertile, whereas fshr-KO and double-KO genetically female fish displayed small ovaries containing many early pre-vitellogenic oocytes and were infertile. Although lhr-KO genetically female fish had normal ovaries with full-grown oocytes, ovulation did not occur. Levels of 17α,20β-dihydroxy-4-pregnen-3-one, which is required for meiotic maturation of oocytes and sperm maturation in teleost fish, were significantly decreased in all KO female medaka ovaries except for double-heteros. Further, 17β-estradiol levels in fshr-KO and double-KO ovaries were significantly lower than those in double-heteros. These findings indicate that LH is necessary for oocyte maturation and FSH is necessary for follicle development, but that neither are essential for spermatogenesis in medaka.

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

“…In addition, the fact that SP males are still able to reproduce suggests that spermatogenesis may not be completely dependent on gonadotropins, and that other factors could compensate for low gonadotropin levels. This hypothesis is consistent with previous knockout studies in male medaka, which demonstrated that the loss of fshb or lhb (46) or double knockout (KO) of fshr and lhr (47,48) does not disrupt spermatogenesis. In male zebrafish, although testis development is delayed significantly, Fsh-deficient fish are still fertile (49).…”

Differential gene expression pattern and plasma sex steroids during testicular development in Genyatremus luteus (Perciforme: Haemulidae) (Bloch, 1790)

“…Although the endocrine system plays crucial role in these processes, the exact mechanisms involved in the sexual maturation of fish remain poorly understood. Studies focused on featuring gonadotropin receptors (fshr and lhr) have been recently carried out to help better understanding the role played by them in regulating sex steroid hormones and testicular development in several fish species (Maugars and Schmitz, 2008;Burow et al, 2020;Kitano et al, 2022).…”

Receptor cavity-based screening reveals potential allosteric modulators of gonadotropin receptors in carp (Cyprinus carpio)

“…A majority of these dysfunctions can be overcome by synthetic or pharmacological stimulation of the receptor in question. In fish, loss of function of FSHR causes masculinization and suppression of ovarian development in female medaka, whereas LHR knockouts were observed to stop ovulation 5, 6 . Recent studies leveraging advances in in silico methods and the availability of whole-crystal structures of GTHRs 7, 8 have greatly increased our understanding of GTH-GTHR binding mechanism and activation.…”