Decoding GnRH neurohormone pulse frequency by convergent signalling modules.

Krasimira Tsaneva-Atanasova, Petros Mina, Christopher J Caunt, Stephen P Armstrong, Craig A McArdle

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Gonadotropin-releasing hormone (GnRH) mediates control of reproduction. It is secreted in pulses and acts via intracellular effectors to activate gonadotrophin secretion and gene expression. Sub-maximal GnRH pulse frequency can elicit maximal responses, yielding bell-shaped frequency-response curves characteristic of genuine frequency decoders. GnRH frequency decoding is therapeutically important (pulsatile GnRH can drive ovulation in assisted reproduction whereas sustained activation can treat breast and prostate cancers), but the mechanisms are unknown. Here, we consider the possibility that it is due to convergence of distinct pulsatile signals at the transcriptome. We develop a model that mirrors wet-laboratory data for activation and nuclear translocation of GnRH effectors (extracellular signal regulated kinase and nuclear factors of activated T-cells) and incorporates transcription. The model predicts genuine frequency decoding when two transcription factors (TFs) converge at a cooperative gate, and shows how optimal pulse frequency could reflect TF activation kinetics and affinities. Importantly, this behaviour is revealed as an emergent feature of the network, rather than an intrinsic feature of a given protein or pathway, and since such network topology is extremely common, may well be widespread in biological systems.
Original languageEnglish
Pages (from-to)170-182
Number of pages13
JournalJournal of the Royal Society, Interface
Volume9
Issue number66
DOIs
Publication statusPublished - 7 Jan 2012

Keywords

  • frequency decoding
  • mathematical model
  • ERK
  • NFAT
  • GnRH

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    Tsaneva-Atanasova, K., Mina, P., Caunt, C. J., Armstrong, S. P., & McArdle, C. A. (2012). Decoding GnRH neurohormone pulse frequency by convergent signalling modules. Journal of the Royal Society, Interface, 9(66), 170-182. https://doi.org/10.1098/rsif.2011.0215