The relationship between basal and regulated Gnrhr expression in rodent pituitary gonadotrophs

Abstract

Hypothalamic GnRH together with gonadal steroids and activins/inhibin regulate its receptor gene (Gnrhr) expression in vivo, which leads to crucial changes in GnRHR numbers on the plasma membrane. This is accompanied by alterations in the gonadotroph sensitivity and responsiveness during physiologically relevant situations. Here we investigated basal and GnRH-regulated Gnrhr expression in rodent pituitary gonadotrophs in vitro. In pituitary cells from adult animals cultured in the absence of GnRH and steroid hormones, the Gnrhr expression was progressively reduced but not completely abolished. The basal Gnrhr expression was also operative in LβT2 immortalized gonadotrophs never exposed to GnRH. In both cell types, basal transcription was sufficient for the expression of functional GnRHRs. Continuous application of GnRH transiently elevated the Gnrhr expression in cultured pituitary cells followed by a sustained fall without affecting basal transcription. Both basal and regulated Gnrhr transcriptions were dependent on the protein kinase C signaling pathway. The GnRH-regulated Gnrhr expression was not operative in embryonal pituitary and LβT2 cells and was established neonatally, the sex-specific response patterns were formed at the juvenile-peripubertal stage and there was a strong correlation between basal and regulated gene expression during development. Thus, the age-dependent basal and regulated Gnrhr transcription could account for the initial blockade and subsequent activation of the reproductive system during development.

Intrinsic and Regulated Gonadotropin-Releasing Hormone Receptor Gene Transcription in Mammalian Pituitary Gonadotrophs

“…In females, Gnrhr expression increases rapidly over the first 2 weeks of development, followed by a transient decline and secondary rise in 7–8 weeks of age. In males, it increases gradually until 5 weeks of age ( 14 – 16 ), followed by a decline toward a steady expression at the adult age ( 11 ). The peak of Gnrhr expression during development correlates well with expression of gonadotropin subunit genes Lhb, Fshb , and Cga in both sexes ( 16 ) as well as with greater LH and FSH secretion in females, but not in males ( 17 ).…”

“…This figure is derived from data published in Ref. ( 11 , 16 , 20 ); no permission is required from the copyright holder.…”

“…In agreement with this, Gnrhr expression is detectable and functional GnRHRs are present in the rat gonadotrophs in vitro even after prolonged period of GnRH absence ( 58 ). Furthermore, prolonged continuous GnRH application does not completely stop Gnrhr transcription (Figure 1 B) ( 11 ). Finally, naïve (never stimulated) αT3-1 and LβT-2 cells express functional Ca 2+ -mobilizing GnRHRs ( 59 , 60 ).…”

“…In rat, mouse, and sheep, the main positive regulator of Gnrhr transcription is GnRH itself ( 11 – 13 , 61 ), depending on the pattern of GnRH application. Figure 1 B illustrates that continuous stimulation of rat pituitary cells induces a transient induction of Gnrhr transcription, with maximal response at 6 h ( 11 , 13 ). Longer GnRH stimulation leads to downregulation in Gnrhr transcription ( 11 , 62 ).…”

“…The differences in the regulation of Gnrhr expression in mammalian species reflect differences in the promoter region of the gene ( 9 , 10 ). The common aspect of regulated transcription of this gene is up- and downregulation by GnRH, depending on the pattern of application ( 11 – 13 ). Other hormones also contribute to regulation of Gnrhr transcription.…”