title: NR5A2 regulates Lhb and Fshb transcription in gonadotrope-like cells in vitro, but is dispensable for gonadotropin synthesis and fertility in vivo.
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.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fortin
authors.forename: Vikas
authors.initials: V
authors.lastname: Kumar
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Ulrich
authors.initials: U
authors.lastname: Boehm
authors.forename: Derek
authors.initials: D
authors.lastname: Boerboom
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bernard
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005298:Fertility / Q000235:genetics*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D052681:Gonadotrophs / Q000166:cytology / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006062:Gonadotropins / Q000096:biosynthesis*; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D011401:Promoter Regions, Genetic; D059368:RNA Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation
chemical_list: D037201:Follicle Stimulating Hormone, beta Subunit; D006062:Gonadotropins; D037101:Luteinizing Hormone, beta Subunit; C431936:Nr5a2 protein, mouse; D059368:RNA Isoforms; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D007987:Gonadotropin-Releasing Hormone
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