Highly regulated pulsatile secretion of the GnRH is essential for reproduction. GnRH pulses act via 7TM receptors to control synthesis and secretion of FSH and LH. GnRH receptors activate a signal-transduction network that includes two parallel pathways mediated by ERK and nuclear factor of activated T cells (NFAT). ERK and NFAT in concert with other effectors mediate transcriptional regulation of FSHβ and LHβ genes following stimulation by pulsatile GnRH. We present a detailed ordinary differential equation based mathematical model for ERK and NFAT signalling pathways. This differs from an earlier model1 in that it is parameterised using data obtained from clonal gonadotroph-derived LβT2 cells and includes a negative feedback loop which describes the effects of receptor internalisation on signalling. Our model closely matches the data on the NFAT and ERK nuclear translocation and GnRH receptor internalisation in LβT2 cells. It is well known that the secretion of FHS and LH is maximal at sub-maximal GnRH pulse frequency,2 but the underlying mechanisms are unclear. We investigate upstream negative feedback as a possiblemechanism for eliciting maximal LHβ and FSHβ expression at sub-maximal GnRH pulse frequency. We show that for the strength of the negative feedback estimated from the data, and for biologically relevant GnRH pulse frequencies, negative feedback alone cannot explain the experimentally observed non-monotonic GnRH pulse frequencyresponse relationship. Instead, we suggest that it reflects down-stream adaptive mechanisms and pathway convergence within the network.
References: 1. K Tsaneva-Atanasova, P Mina, CJ Caunt, SP Armstrong & CA McArdle. Decoding GnRH neurohormone pulse frequency by convergent signalling modules. J R Soc Interface 2012 9 170182.
2. Thompson IR & Kaiser UB. GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression. Mol Cell Endocrinol 2014 385 2835.