Decoding pulsatile GnRH signals

Krasimira Tsaneva-Atanasova (University of Bristol (Engineering Mathematics))

Thursday 9th February, 2012 14:00-15:00 Maths-Stats Bldg, LT 325


Gonadotrophin-releasing hormone (GnRH) is a hormone released from the brain to control the secretion of reproductive hormones. Pulsatile GnRH can increase fertility (e.g. in IVF programmes) whereas sustained GnRH reduces fertility (and is used to treat hormone-dependent cancer) but the ways in which the GnRH receptor and its intracellular signalling cascade decode these kinetic aspects of stimulation are essentially unknown. In addition, our knowledge is scarce of the intracellular mechanisms that govern frequency modulation of gonadotropins secretion, much less how such fine-tuning is regulated by different signal inputs. There is an emerging concept that differential expression of gonadotropin subunits gene is associated with modification of activation and/or stability of important regulatory proteins and transcription factors. We present a signalling pathway model of GnRH-dependent transcriptional activation developed to dissect the dynamic mechanisms of differential regulation of gonadotropin subunits gene. The model incorporates key signalling molecules, including extracellular-signal regulated kinase (ERK) and calcium-dependent activation of Nuclear Factor of Activated T-Cells (NFAT), as well as translocation of activated/inactivated ERK and NFAT across the nuclear envelope. We show that simulations with varying in dose and frequency GnRH pulsatile inputs agree very well with experimental measurements of GnRH-dependent ERK and NFAT responses. In silico experiments designed to probe trancriptional effects downstream of ERK and NFAT reveal that interaction between transcription factors is sufficient to account for frequency discrimination. Finally, using parameter sensitivity and bifurcation analysis we identify key parameter relationships that govern differential expression of gonadotropin subunits gene.

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