Abstract
Successful mammalian reproduction depends on proper synthesis of the pituitary-derived glycoprotein hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Several transcription factors cooperate to activate cell-specific and hormone-regulated expression of the gonadotropin beta subunits (Lhb and Fshb). Among these, NR5A1 (steroidogenic factor 1; SF1) has been shown to directly bind to the Lhb promoter, mediate basal and gonadotropin-releasing hormone (GnRH)-stimulated Lhb transcription, and possibly directly regulate Fshb expression. Recently, the closely-related NR5A2 was shown to activate the rat Lhb promoter in vitro. Here, we further characterized the role of NR5A2 in regulating gonadotropin synthesis. Ectopically expressed NR5A2 directly activated the murine Lhb promoter in a manner identical to that of NR5A1, whereas neither factor activated the murine Fshb promoter. In LβT2 gonadotrope-like cells, depletion of endogenous NR5A1 or NR5A2 impaired basal and GnRH-stimulated Lhb and Fshb transcription. To analyze the physiological role of NR5A2 in gonadotropes in vivo, we generated mice with a gonadotrope-specific deletion of Nr5a2. In contrast with our in vitro data, these mice had normal pituitary Lhb and Fshb expression and intact fertility. Together, our data establish that NR5A2 can act in a non-redundant manner to regulate Lhb and Fshb transcription in vitro, but is dispensable in vivo.
Highlights
The pituitary-derived gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are critical regulators of gonadal function and fertility in mammals
As our in vitro data suggested a role for NR5A2 in the regulation of both Lhb and Fshb transcription, we examined the expression of these genes in the pituitaries of 6 week-old Nr5a2fl/fl; GnrhrGRIC/+ mice and Nr5a2fl/fl littermates
We observe that the full-length and pituitary NR5A2 isoforms are functionally indistinguishable in their abilities to activate the murine Lhb promoter and do so to an extent and in a manner comparable to NR5A1
Summary
The pituitary-derived gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are critical regulators of gonadal function and fertility in mammals. LH and FSH are dimeric glycoproteins composed of a common a subunit (aGSU or CGA) and unique b subunits (LHB and FSHB), which confer biological specificity. Lhb and Fshb expression, which is ratelimiting in the production of the mature hormones, is under the control of several endocrine, paracrine, and autocrine factors [1,2]. Most important for Lhb production is gonadotropinreleasing hormone (GnRH). LH in turn regulates steroidogenesis by the testes and ovaries, and is critical for ovulation and luteinization in females [5,6]
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