Transcriptional regulation of the FSH receptor: New perspectives

Abstract

The cell-surface receptor for the gonadotropin follicle-stimulating hormone (FSH) is expressed exclusively on Sertoli cells of the testis and granulosa cells of the ovary. FSH signal transduction through its receptor (Fshr) is critical for the timing and maintenance of normal gametogenesis in the mammalian gonad. In the 13 years since the gene encoding Fshr was first cloned, the mechanisms controlling its transcription have been extensively examined, but a clear understanding of what drives its unique cell-specificity remains elusive. Current knowledge of basal Fshr transcription highlights the role of an E-box in the proximal promoter which is bound by the basic helix-loop-helix transcription factors upstream stimulatory factor 1 (Usf1) and Usf2. Recent studies utilizing knockout mice and chromatin immunoprecipitation validated the importance of Usf to Fshr transcription and demonstrated a sexually dimorphic requirement for the Usf proteins to maintain normal Fshr expression. Studies have also shown that the promoter region itself is insufficient for appropriate Fshr expression in transgenic mice, indicating Fshr transcription depends on regulatory elements that lie outside of the promoter. Identification of such elements has been propelled by recent availability of genome sequence data, which facilitated studies using comparative genomics, DNase I hypersensitivity mapping, and transgenic analysis with large fragments of DNA. This review will focus on the current understanding of transcriptional regulatory processes that control expression of rat Fshr, including recent advances from our laboratory.

In Vivo Regulation of Follicle-Stimulating Hormone Receptor by the Transcription Factors Upstream Stimulatory Factor 1 and Upstream Stimulatory Factor 2 Is Cell Specific

“…Recent transgenic analysis of a 413-kb yeast artificial chromosome corroborated the promoter deficiency and added additional support for the importance of distal regulatory regions in Fshr transcription (38). Despite containing a large genomic region with the entire Fshr coding sequence (from 97 kb upstream of exon 1 to 57 kb downstream of exon 10), this transgene failed to express in either Sertoli or granulosa cells (14). Furthermore, like the two previous promoter studies that investigated cellular expression, YAC transgene expression was observed in the testis but only ectopically in germ cells.…”

“…In addition to controlling Fshr basal transcription, the E-box and USF were required to convey transcriptional signals that activate Fshr by the orphan nuclear receptor NR5A1, better known as steroidogenic factor 1 (SF-1) (13,15,21). Thus, the E-box, together with USF1 and USF2, likely coordinates Fshr transcription by integrating signals from other transcription factors bound elsewhere on the promoter or to more distal regulatory elements (14).…”

Expression of a Tumor-Related Gene Network Increases in the Mammalian Hypothalamus at the Time of Female Puberty

“…Although the best-known function of Foxp1 is to promote development of the B cell lineage of the immune system (65); it is also expressed in the hypothalamus, in which it functions to increase food intake and body weight, and it is negatively regulated by leptin (66); Usf2 is a member of the evolutionary conserved family of basic-helix-loop-helix-leucine zipper transcription factors (67); recognized by an E-box binding motif present in various gene promoters, it plays an important role in the regulation of gene transcription by recruiting chromatin remodeling enzymes (67). An involvement of Usf2 in the control of reproductive function was recently shown by the finding that Usf2 controls the expression of the FSH receptor gene (68). FSH receptors mediate the actions of the gonadotropin FSH on the hypothalamic-pituitary-gonadal axis.…”

The Aryl Hydrocarbon Receptor Regulates Mouse Fshr Promoter Activity Through an E-Box Binding Site1

“…FSH and its relative, LH, are major components of the hypothalamic-pituitary-gonad axis, which regulates reproductive function and ultimately the production of gametes and fertility [12]. By binding FSH receptor (FSHR) located on the membrane of ovarian granulosa cells, FSH promotes the development of immature follicles, eventually leading to the formation of mature preovulatory follicles [13,14].…”