Disease relevance of Fshb

• This synergistic interaction is specific to FSHbeta, because only additive effects of these two hormones are observed on LH beta-subunit, GnRH receptor, and mouse mammary tumor virus gene expression [1].
• The pituitary tumors express the alpha-, FSHbeta-, and LHbeta-subunits and the GnRH-R messenger RNA, all markers of a gonadotrope but not of other anterior pituitary cell lineages [2].
• Anterior pituitary pathology progressed from diffuse gonadotroph hyperplasia to nodular adenomas with persistent, but decreasing, immunoreactivity for FSHbeta and LHbeta [3].
• The follicle-stimulating hormone (FSH) beta- and common alpha-subunits are expressed in mouse testis, as determined in wild-type mice and those transgenic for the FSH beta-subunit/herpes simplex virus thymidine kinase fusion gene [4].
• Findings in men are controversial, since FSHbeta inactivation is related to azoospermia, whereas the cognate receptor inactivation only suppresses spermatogenesis without causing absolute infertility [5].

High impact information on Fshb

• Minimal data has been accumulated so far involving human mutations in the FSH beta, LH beta, or the gonadotropin receptor genes [6].
• To generate animal models for human diseases involving the gonadotropin signal transduction pathway, we produced mice deficient in the FSH beta subunit and therefore in FSH using ES cell technology [6].
• We recently found that mice deficient in the beta-subunit of follicle-stimulating hormone (FSHbeta) are protected from bone loss despite severe estrogen deficiency [7].
• Here, we identify elements in the mouse FSHbeta promoter responsible for GnRH-mediated induction utilizing the LbetaT2 cell line that endogenously expresses FSH [8].
• Transient transfection of each receptor, along with ligand treatment, stimulates the mouse FSHbeta promoter, but induction is severely diminished using receptors that lack the ability to bind DNA, indicating that induction is likely through direct DNA binding [9].

Biological context of Fshb

• Analysis of ovarian gene expression in follicle-stimulating hormone beta knockout mice [10].
• Furthermore, in transient transfections an ovine FSHbeta 5'-regulatory region (5.5 kb) confers LbetaT2 cell-specific expression to a reporter gene compared with other pituitary and nonpituitary cell lines [11].
• Here we show that the rat GnRH-R promoter drives the expression of the reporter gene in pituitary cells expressing the LHbeta and/or FSHbeta subunit but not in TSHbeta- or GH-positive cells [12].
• Although components of the FSH null phenotype may be caused by partial cyclin D2 loss of function, these findings indicate that the mechanisms of granulosa cell cycle arrest in FSHbeta knockout mice are distinct from those of cycle withdrawal at luteinization [10].
• In addition, GnRH stimulates both the FSHbeta and LHbeta regulatory regions, specifically in LbetaT2 cells [11].

Anatomical context of Fshb

• It is expressed at high levels in the Fshb knockout mice and in a compartmentalized manner in the granulosa cell/Sertoli cell tumors that develop in the Inha knockout mice [13].
• It is nearly undetectable in ovaries of Fshb knockout mice, which develop preantral follicles but have no luteal cells [13].
• These same expression patterns were also seen in oocytes from Gdf9(-/-) and Fshb(-/-) mice [14].
• Within the anterior pituitary gland, activins stimulate FSH synthesis in an autocrine/paracrine fashion by stimulating transcription of the FSHbeta subunit gene [15].
• These data suggest that testosterone feedback inhibits the human FSH beta subunit gene directly at the pituitary gland in addition to the indirect mechanism of GnRH suppression [16].

Associations of Fshb with chemical compounds

• Production of the beta-subunit of FSH is the rate-limiting step in FSH synthesis, and a number of peptide and steroid hormones within the reproductive axis have been found to regulate transcription of the FSH beta-subunit gene [1].
• To test this hypothesis, we used an LHbeta promoter to immortalize a cell that represents a subsequent stage of gonadotrope differentiation (expression of alpha-subunit, GnRH receptor, and LH beta-subunit but not FSH beta-subunit) [17].
• FSHbeta primary transcript and mRNA levels were increased within 30-60 min, but these effects were blocked by preincubation with the transcription inhibitor actinomycin-D, suggesting that the FSHbeta gene is a direct target of the activin signal transduction cascade [15].
• Thus, during GnRHA inhibition of endogenous GnRH activity, androgen uniquely stimulates FSH beta mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)[18]
• Furthermore, the in vitro data indicate that the suppression of human FSH beta gene expression is at least partly a direct androgen effect that does not require aromatization of testosterone to estradiol [16].
• Disruption of Smad binding to the promoter with a Smad protein lacking the DNA-binding domain or an FSHbeta promoter containing mutated activin-response elements prevents the synergistic enhancement of FSHbeta transcription [19].

Physical interactions of Fshb

• Nuclear factor Y and steroidogenic factor 1 physically and functionally interact to contribute to cell-specific expression of the mouse Follicle-stimulating hormone-beta gene [20].

Regulatory relationships of Fshb

• Collectively, these data suggest that activins use both SMAD2- and SMAD3-dependent mechanisms to stimulate FSHbeta transcription in mouse gonadotrope cells [15].
• We identify binding sites for the orphan nuclear receptor steroidogenic factor-1 and the heterotrimeric transcription factor nuclear factor Y and show that these elements functionally interact to regulate FSH beta gene expression in an L beta T2 cell-specific manner [20].
• Daily injections of 1 microgram GnRH for 14 days induced expression of the human FSH beta gene in male and female mice [16].
• These results suggest that TSH beta overexpression in TU-SPCs must be caused by a deprivation of TH which plays a role in the negative feedback system and that FSH beta expression also might be enhanced by mechanisms similar to those of TSH beta, probably due to certain overlapping of the endocrinological regulation of TSH and FSH in H. retardatus [21].

Other interactions of Fshb

• TSH beta-subunit transcripts appear several days later but precede transcription of the GH and FSH beta and LH beta-subunit genes [22].
• Regulation of FSHbeta and GnRH receptor gene expression in activin receptor II knockout male mice [23].
• Compared to castrated wild-type (WT) mice, FSHbeta mRNA levels in the pituitaries of Acvr2 null mice were significantly downregulated in the absence of gonadal feedback [23].
• Using RT-PCR, we show that these cells synthesize FSH beta- subunit messenger RNA, which is induced by activin and inhibited by follistatin [11].
• Transient transfection of SMAD3, but not SMADs 1, 2, 4, 5, or 8, stimulated endogenous FSHbeta mRNA levels [15].

Analytical, diagnostic and therapeutic context of Fshb

• Ovariectomy led to increased amounts of FSH-beta but not LH-beta messenger RNA, which suggested a pituitary defect [24].
• Castration increased FSHbeta mRNA levels only in WT males, but significantly increased serum FSH levels in both genotypes [25].
• The presence of this transgene [and thus the interspecies hybrid (i.e. mouse alpha:human FSHbeta hormone)] in the background of mouse FSHbeta deficiency completely restored the testis size, sperm number, and motility defects to levels comparable to those seen in control male mice [26].
• FSH-beta mRNA was only expressed in pituitary gland out of various tissues examined and can be up-regulated by gonadotropin-releasing hormone in pituitary tissue culture as estimated by real-time quantitative PCR [27].

References