Mechanisms for pulsatile regulation of the gonadotropin subunit genes by GNRH1

Abstract

The frequency of gonadotropin-releasing hormone (GNRH1, or GnRH) pulses secreted from the hypothalamus determine the ratios of the gonadotropin subunit genes luteinizing hormone beta (Lhb), follicle-stimulating hormone beta (Fshb) and the common alpha-glycoprotein subunit gene (Cga) transcribed in the anterior pituitaries of mammals. Fshb is preferentially transcribed at slower GNRH1 pulse frequencies, whereas Lhb and Cga are preferentially transcribed at more rapid pulse frequencies. Producing the gonadotropins in the correct proportions is critical for normal fertility. Currently, there is no definitive explanation for how GNRH1 pulses differentially activate gonadotropin subunit gene transcription. Several pathways may contribute to this regulation. For example, GNRH1-regulated GNRH1-receptor concentrations may lead to variable signaling pathway activation. Several signaling pathways are activated by GnRH, including mitogen-activated protein kinase, protein kinase C, calcium influx, and calcium-calmodulin kinase, and these may be preferentially regulated under certain conditions. In addition, some signaling proteins feed back to downregulate their own levels. Other arms of gonadotroph signaling appear to be regulated by synthesis, modification, and degradation of either transcription factors or regulatory proteins. Finally, the dynamic binding of proteins to the chromatin, and how that might be regulated by chromatin-modifying proteins, is addressed. Oscillations in expression, modification, and chromatin binding of the proteins involved in gonadotropin gene expression are likely a link between GNRH1 pulsatility and differential gonadotropin transcription.