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1.
Endocrinology ; 163(11)2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-35957608

RESUMO

The inhibins control reproduction by suppressing follicle-stimulating hormone synthesis in pituitary gonadotrope cells. The newly discovered inhibin B coreceptor, TGFBR3L, is selectively and highly expressed in gonadotropes in both mice and humans. Here, we describe our initial characterization of mechanisms controlling cell-specific Tgfbr3l/TGFBR3L transcription. We identified two steroidogenic factor 1 (SF-1 or NR5A1) cis-elements in the proximal Tgfbr3l promoter in mice. SF-1 induction of murine Tgfbr3l promoter-reporter activity was inhibited by mutations in one or both sites in heterologous cells. In homologous cells, mutation of these cis-elements or depletion of endogenous SF-1 similarly decreased reporter activity. We observed nearly identical results when using a human TGFBR3L promoter-reporter. The Tgfbr3l gene was tightly compacted and Tgfbr3l mRNA expression was essentially absent in gonadotropes of SF-1 (Nr5a1) conditional knockout mice. During murine embryonic development, Tgfbr3l precedes Nr5a1 expression, though the two transcripts are fully colocalized by embryonic day 18.5 and thereafter. Collectively, these data indicate that SF-1 directly regulates Tgfbr3l/TGFBR3L transcription and is required for postnatal expression of the gene in gonadotropes.


Assuntos
Regulação da Expressão Gênica , Receptores de Fatores de Crescimento Transformadores beta , Fator Esteroidogênico 1 , Animais , Feminino , Hormônio Foliculoestimulante/metabolismo , Proteínas de Homeodomínio/metabolismo , Inibinas/genética , Inibinas/metabolismo , Camundongos , Gravidez , RNA Mensageiro , Receptores de Fatores de Crescimento Transformadores beta/genética , Fator Esteroidogênico 1/genética , Fator Esteroidogênico 1/metabolismo
2.
Sci Adv ; 7(51): eabl4391, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34910520

RESUMO

Follicle-stimulating hormone (FSH), a key regulator of ovarian function, is often used in infertility treatment. Gonadal inhibins suppress FSH synthesis by pituitary gonadotrope cells. The TGFß type III receptor, betaglycan, is required for inhibin A suppression of FSH. The inhibin B co-receptor was previously unknown. Here, we report that the gonadotrope-restricted transmembrane protein, TGFBR3L, is the elusive inhibin B co-receptor. TGFBR3L binds inhibin B but not other TGFß family ligands. TGFBR3L knockdown or overexpression abrogates or confers inhibin B activity in cells. Female Tgfbr3l knockout mice exhibit increased FSH levels, ovarian follicle development, and litter sizes. In contrast, female mice lacking both TGFBR3L and betaglycan are infertile. TGFBR3L's function and cell-specific expression make it an attractive new target for the regulation of FSH and fertility.

3.
Elife ; 102021 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-34939930

RESUMO

Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G-protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.


Assuntos
Fertilidade , Hormônio Luteinizante/metabolismo , Receptores LHRH/química , Receptores LHRH/fisiologia , Animais , Galinhas , Feminino , Hormônio Foliculoestimulante/metabolismo , Camundongos , Camundongos Transgênicos , Folículo Ovariano/fisiologia , Receptores Acoplados a Proteínas G/fisiologia
4.
Reproduction ; 161(3): 289-294, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33300886

RESUMO

Ovarian follicle development is regulated by locally produced TGFß superfamily members. The TGFß type III receptor (TGFBR3, or betaglycan), which regulates the actions of diverse TGFß ligands, including inhibins, is expressed in different ovarian cell types. However, its functional roles in the ovary have not been investigated in vivo. Here, we ablated Tgfbr3 in murine oocytes using the Cre-loxP system. Oocyte-specific Tgfbr3 knockout (cKO) females were fertile, producing litters of similar size and frequency as controls. Their ovarian weights and histology were also normal. Though we confirmed efficient recombination of the floxed alleles, we did not detect Tgfbr3 mRNA in purified oocytes from superovulated cKO or control mice. These results challenge earlier observations of betaglycan protein expression in this cell type. Regardless, Tgfbr3 in the murine oocyte is clearly dispensable for female fertility.


Assuntos
Proteoglicanas , Receptores de Fatores de Crescimento Transformadores beta , Animais , Feminino , Fertilidade , Camundongos , Oócitos , Proteoglicanas/genética , Receptores de Fatores de Crescimento Transformadores beta/genética
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