REGULATION OF GONADOTROPIN SUBUNIT GENE-EXPRESSION

Physiological regulation of gonadotrophin subunit gene expression was investigated in vivo by cDNA-mRNA hybridization from individual pituitary glands from rats and mice. Common alpha, LH-beta, FSH-beta mRNA increased in a time-dependent manner after orchidectomy and ovariectomy of rats, the increases being prevented by testosterone and oestradiol, respectively, in male and female rats. Increases in all three subunit mRNAs after gonadectomy were prevented by a GnRH antagonist and antiserum, and were reduced by the same treatments in intact rats, indicating their dependence on endogenous GnRH. Further evidence for GnRH influences on gonadotrophin gene activation comes from pulsatile GnRH treatment of GnRH deficient hypogonadotrophic hypogonadal mice in which this induced alpha and LH-beta mRNA to supranormal and normal values, respectively. Pituitary desensitization with GnRH agonist infusion markedly suppressed LH-beta and FSH-beta mRNA levels and pituitary LH accumulation, but paradoxically increased alpha subunit mRNA to castrate levels in intact rats and failed to suppress alpha mRNA in castrated rats. These results indicate the divergent regulation of alpha and specific LH-beta/FSH-beta mRNA in vivo and that the latter are closely related to LH/FSH synthesis and secretion and physiological GnRH stimulation of the pituitary. In-vitro studies suggest that physiological GnRH reduces transcription from beta subunit genes and also stabilizes their mRNAs, possibly by altering mRNA length. Preliminary studies to investigate regulatory elements in the 5' region of the LH-beta gene suggest the presence of an atypical cAMP responsive element since an LH-beta-CAT construct can be induced by 3-fold in a transient heterologous cell expression