Molecular cloning, structure, and expression of a testicular follitropin receptor with selective alteration in the carboxy terminus that affects signaling function

Yarney, T.A.; Jiang, L.G.; Khan, Haseena; Macdonald, Elizabeth; Laird, Dale W.; Sairam, M.R.

doi:10.1002/(sici)1098-2795(199712)48:4<458::aid-mrd6>3.0.co;2-p

Cited by 36 publications

(26 citation statements)

References 47 publications

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“…FSHR4 comprises only exons 1-4. FSHR4 is considered as a soluble receptor isoform, whereas FSHR2 is considered to be a dominant negative receptor isoform (Yarney et al 1997a).…”

Section: R37mentioning

confidence: 99%

“…The first paper challenging Khan et al (1993) Cloned and characterized two alternately spliced forms of sheep testicular FSHR mRNA. A smaller receptor cDNA of 727 bp (from exon 1 to exon 4) codes for 134 amino acids and 1.1 kb cDNA clone (extending up to the 8th exon) codes for a mature protein of 259 amino acids Yarney et al (1997a) By PCR, northern analysis, cloning, and transfection studies on HEK 293 cells, a 2.4 kb transcript with absent cAMPinduced functions was reported. It consisted of nucleotides K121 to 1924 of FSHR and a novel 3' region comprising nucleotides 1925-2307 that encoded a protein of 670 amino acids containing the entire extracellular domain and an altered C-terminus Yarney et al (1997b) Reported five distinct mRNA transcripts in male lambs of two different sheep genotypes.…”

Section: R39mentioning

confidence: 99%

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FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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Despite extensive research, genetic basis of premature ovarian failure (POF) and ovarian cancer still remains elusive. It is indeed paradoxical that scientists searched for mutations in FSH receptor (FSHR) expressed on granulosa cells, whereas more than 90% of cancers arise in ovary surface epithelium (OSE). Two distinct populations of stem cells including very small embryonic-like stem cells (VSELs) and ovarian stem cells (OSCs) exist in OSE, are responsible for neo-oogenesis and primordial follicle assembly in adult life, and are modulated by FSH via its alternatively spliced receptor variant FSHR3 (growth factor type 1 receptor acting via calcium signaling and the ERK/MAPK pathway). Any defect in FSH-FSHR3-stem cell interaction in OSE may affect folliculogenesis and thus result in POF. Ovarian aging is associated with a compromised microenvironment that does not support stem cell differentiation into oocytes and further folliculogenesis. FSH exerts a mitogenic effect on OSE and elevated FSH levels associated with advanced age may provide a continuous trigger for stem cells to proliferate resulting in cancer, thus supporting gonadotropin theory for ovarian cancer. Present review is an attempt to put adult ovarian biology, POF, aging, and cancer in the perspective of FSH-FSHR3-stem cell network that functions in OSE. This hypothesis is further supported by the recent understanding that: i) cancer is a stem cell disease and OSE is the niche for ovarian cancer stem cells; ii) ovarian OCT4-positive stem cells are regulated by FSH; and iii) OCT4 along with LIN28 and BMP4 are highly expressed in ovarian cancers.Reproduction (2015) 149 R35-R48

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“…FSHR4 comprises only exons 1-4. FSHR4 is considered as a soluble receptor isoform, whereas FSHR2 is considered to be a dominant negative receptor isoform (Yarney et al 1997a).…”

Section: R37mentioning

confidence: 99%

Section: R39mentioning

confidence: 99%

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Bhartiya

Singh

2015

Reproduction

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“…Alternatively spliced variants of the FSHR gene in rat and sheep have been observed to result in the soluble form of the protein or modification of the C-terminal domain of the receptor (Sairam et al 1996, Yarney et al 1997. In humans, alternate splicing of exon 9 in normal testicular tissue has been reported, which suggests that this spliced variant does not affect the FSHR function in testis (Gromoll et al 1992).…”

Section: Alternatively Spliced Variants Of the Fshr Genementioning

confidence: 99%

Mutations and polymorphisms in FSH receptor: functional implications in human reproduction

Desai¹,

Roy²,

Mahale³

2013

Reproduction

116

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FSH brings about its physiological actions by activating a specific receptor located on target cells. Normal functioning of the FSH receptor (FSHR) is crucial for follicular development and estradiol production in females and for the regulation of Sertoli cell function and spermatogenesis in males. In the last two decades, the number of inactivating and activating mutations, single nucleotide polymorphisms, and spliced variants of FSHR gene has been identified in selected infertile cases. Information on genotype-phenotype correlation and in vitro functional characterization of the mutants has helped in understanding the possible genetic cause for female infertility in affected individuals. The information is also being used to dissect various extracellular and intracellular events involved in hormone-receptor interaction by studying the differences in the properties of the mutant receptor when compared with WT receptor. Studies on polymorphisms in the FSHR gene have shown variability in clinical outcome among women treated with FSH. These observations are being explored to develop molecular markers to predict the optimum dose of FSH required for controlled ovarian hyperstimulation. Pharmacogenetics is an emerging field in this area that aims at designing individual treatment protocols for reproductive abnormalities based on FSHR gene polymorphisms. The present review discusses the current knowledge of various genetic alterations in FSHR and their impact on receptor function in the female reproductive system. Reproduction (2013) 146 R235-R248

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“…Accordingly, a more complex model introduces the concept that alternative downstream pathways are triggered by particular glycosylation variants of the gonadotropin, independent of receptor-binding affinity. In this model, the same receptor or its membrane-expressed variants [38,39] may evoke a spectrum of responses reflected in activation/inhibition of various intracellular signaling pathways [39,40].…”

Section: Single-cell-type Assaysmentioning

confidence: 99%

Impact of Carbohydrate Heterogeneity in Function of Follicle-Stimulating Hormone: Studies Derived from in Vitro and in Vivo Models1

Ulloa‐Aguirre¹,

Timossi²,

Barrios-De-Tomasi³

et al. 2003

Biology of Reproduction

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Carbohydrates attached to the protein core of glycoprotein hormones influence a number of intracellular and extracellular processes. As with other members of the glycoprotein hormone family, FSH is produced and released as an array of isoforms that differ from each other in the structure of their oligosaccharide attachments. In this review, we discuss how carbohydrate heterogeneity can impact on FSH action in different in vitro and in vivo systems. We present evidence for diverse effects of distinct charge isoforms at the target cell level, including differential and unique effects on various end responses, and discuss how the use of multiple cell-type assays has allowed identification of some specific effects of FSH isoforms on different cell populations and follicle compartments as well as oocyte maturation. Finally, we discuss recent information on the ability of naturally occurring and laboratory manufactured FSH isoforms to evoke particular effects on granulosa cell function and ovarian follicular maturation in vivo. Such studies have provided evidence that the type(s) of FSH signal delivered may in fact regulate distinct biological outcomes irrespective or in addition to outcomes dictated solely by clearance rate differences.

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Molecular cloning, structure, and expression of a testicular follitropin receptor with selective alteration in the carboxy terminus that affects signaling function

Cited by 36 publications

References 47 publications

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

FSH–FSHR3–stem cells in ovary surface epithelium: basis for adult ovarian biology, failure, aging, and cancer

Mutations and polymorphisms in FSH receptor: functional implications in human reproduction

Impact of Carbohydrate Heterogeneity in Function of Follicle-Stimulating Hormone: Studies Derived from in Vitro and in Vivo Models1

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