Disease relevance of Fshr

• The uterine weight in 12-month-old Fshr +/- mice increased 2-fold, and most retired breeders (those that stopped breeding earlier than our wild-type females) developed unilateral uterine masses that appeared similar to several abnormalities that also occur in women and associated with infertility [1].
• Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice [2].
• The tumor burden caused weight loss and cachexia in follitropin receptor knockout mice [3].
• We recently produced filamentous phages displaying FSHR fragments overlapping residues 18-38, which, if injected in animals, induced anti-FSH receptor immunity capable of inhibiting hormone binding [4].
• Hyperplasia of gonadotropin-secreting cells in FSH receptor knock-out male mice [5].

High impact information on Fshr

• In addition, there was an increase in PDGF receptor alpha (PDGFRalpha) and a decrease in PDGFbeta expression in the granulosa cells, similar to what has been found in follitropin receptor knockout mice [6].
• FSH-R-deficient males are fertile but display small testes and partial spermatogenic failure [7].
• The phenotype of FSH-R -/- mice is reminiscent of human hypergonadotropic ovarian dysgenesis and infertility [7].
• Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance [7].
• FSH-R-deficient females display thin uteri and small ovaries and are sterile because of a block in folliculogenesis before antral follicle formation [7].

Biological context of Fshr

• Fshr null females are sterile because of failure of follicular maturation, ovulation, and estrogen deficiency [1].
• Role of follitropin receptor signaling in nuclear protein transitions and chromatin condensation during spermatogenesis [8].
• In the adult, absence of FSHR signaling prolongs retention of mono-uH2A, leading to impair transition of basic nucleoproteins and chromatin remodeling during mouse spermatogenesis [8].
• Aromatase gene expression, a prime marker for FSH effect, is found only in IGF-I/FSHR-positive follicles, showing that these are healthy, gonadotropin-responsive follicles [9].
• Thus, the phenotypes evident in these genetically altered FSH-R mutants may provide an experimental system to explore the effects of estrogenic compounds on different targets including the ovary in a nonsurgical setting [2].

Anatomical context of Fshr

• Follitropin receptor (FSHR) in testicular Sertoli cells mediates signaling by pituitary follitropin (FSH) promoting intercellular communication with germ cells for normal spermatogenesis [8].
• Other down-regulated genes included: Cyp19a1, Fshr, Inhb, and the oocyte factors Zp1-3 and Gja4 [10].
• The results indicate, therefore, that Sertoli cells regulate the development of Leydig cell number and that constitutive activity within the FSHR is sufficient to stimulate this process [11].
• Age-related neurodegenerative changes in the central nervous system of estrogen-deficient follitropin receptor knockout mice [12].
• Both promoter elements seem to be still under tissue specific control, since neither LH receptor nor FSH receptor promoter activity was detectable in another cell line (CHO) investigated [13].

Associations of Fshr with chemical compounds

• These transformations were not present in either wild-type mice or the estrogen-deficient Fshr null females at any age [1].
• Targeted disruption of the receptor for glycoprotein hormone, FSH (FSH-R) causes a gene dose-related endocrine and gametogenic abnormality in female mice [2].
• As all these changes occurred in a background of normal circulating testosterone levels, we may conclude that the delay in testicular development is a consequence of the loss of FSH-receptor signaling [14].
• The first activating mutation of the FSH receptor (FSHR*D567G) was identified in a gonadotropin-deficient hypophysectomized man who exhibited persistent spermatogenesis and fertility with only androgen replacement [15].
• The murine luteinizing hormone and follicle-stimulating hormone receptor genes: transcription initiation sites, putative promoter sequences and promoter activity [13].

Physical interactions of Fshr

• This study provides the first in vivo evidence that USF1 and USF2 bind the Fshr promoter and revealed differences between Sertoli and granulosa cells in compensatory responses to USF loss and the USF dimeric composition required for Fshr transcription [16].

Regulatory relationships of Fshr

• These data suggest that ovarian IGF-I expression serves to enhance granulosa cell FSH responsiveness by augmenting FSHR expression [9].

Other interactions of Fshr

• Thus lack of FSHR signaling impairs expression of TP1/2 and PRM-2 at an early stage of post-natal development causing delayed spermatogenesis [8].
• We have examined this directly using two mouse models with null mutations in either the FSH beta-subunit (FSHbetaKO mice) or the FSH receptor (FSHRKO mice) [11].
• Regulation of luteinizing hormone-receptor and follicle-stimulating hormone-receptor messenger ribonucleic acid levels during development in the neonatal mouse ovary [17].
• In hpg/hpg animals, FSH-receptor mRNA levels were normal up to Day 7 but failed to increase thereafter [17].
• Further development of LH-receptor mRNA levels is gonadotropin-dependent although FSH-receptor mRNA levels continue to increase independently until early secondary follicles are present [17].

Analytical, diagnostic and therapeutic context of Fshr

• Molecular cloning of the mouse follicle-stimulating hormone receptor complementary deoxyribonucleic acid: functional expression of alternatively spliced variants and receptor inactivation by a C566T transition in exon 7 of the coding sequence [18].
• Molecular cloning of the mFSHR cDNA was carried out by reverse transcription-polymerase chain reaction (RT-PCR) using 129/Sv mouse testicular RNA and primers complementary to the rat or the partially characterized mouse FSHR sequence [18].
• The largest transcript was the expected size from the position of the PCR primers (on exons 1 and 10) and sequencing confirmed that it was derived from FSH receptor mRNA [19].
• Taken together these data suggest a key role for the FSH receptor in maintaining Sertoli cells to sustain normal sperm numbers and proper shapes of their heads and tails [20].
• Treatment of 2-d-old rat ovaries in organ culture with NGF increased FSH receptor (FSHR) mRNA within 8 h of exposure [21].

References