New research challenges our understanding of cell communication

August 3, 2011

Cells often communicate with one another using pulsatile signals, where information is conveyed in pulse frequency as well as amplitude. This raises the question of how cells decode pulsatile signals, a question that lies at the core of our understanding of how the brain controls reproduction.

A by Dr Krasimira Tsaneva-Atanasova, Lecturer in the Department of Engineering Mathematics and Craig McArdle, Professor of in the School of Clinical Sciences, that challenges conventional wisdom regarding pulsatile GnRH signaling is published ahead of print in the Journal of the Royal Society Interface.

The mechanisms underlying cellular pulse frequency decoding are poorly understood. In this system, a small number of neurons in the brain secrete a protein hormone (gonadotrophin-releasing hormone – GnRH) that acts on cells in the pituitary gland to stimulate the synthesis and secretion of two gonadotrophin hormones (LH and FSH). These, in turn, control production of egg cells and sex steroid hormones in the gonads and in this way, GnRH mediates central control of reproduction. GnRH is secreted in bursts (normally pulses of a few minutes duration every 30 minutes to eight hours in humans) and its effects are dependent upon pulse frequency.

Pulsatile GnRH drives pubertal development and also causes the cyclical surge in protein hormone secretion that drives ovulation in women, but when pulse frequency is too high this can reduce secretion, causing a chemical castration that is used in the treatment of steroid hormone dependent cancers. In essence, the physiology and therapeutic manipulation of the reproductive system is underpinned by bell-shaped frequency response relationships in which sub-maximal GnRH pulse frequencies elicit maximal responses.

The mechanisms explaining this relationship are largely unknown but researchers have begun to use mathematical and wet-lab modeling approaches to solve the problem. For many years negative feedback has been assumed to underlie reduced responses at high pulse frequency and the McArdle lab have used a live cell imaging approach to test for such feedback.  By expressing signalling proteins tagged to fluorescent marker proteins, effects of GnRH on two signalling pathways (ERK and NFAT pathways) were monitored during trains of GnRH pulses and the anticipated negative feedback simply didn’t occur (Armstrong et al. 2009,2010).

Dr Tsaneva-Atanasova then developed a mathematical model for GnRH signalling that faithfully mirrors the wet-lab data. Extending the model to predict effects of pulsatile GnRH on gonadotrophin synthesis predicted bell-shaped frequency-response relationships when the two pathways converge in a co-operative manner at gene promoters. In this way genuine frequency decoding occurs as an emergent feature of the signalling network, even when individual proteins or modules within the network do not function as stand-alone frequency decoders.

Dr Tsaneva-Atanasova said: “The direct importance of our work lies in the potential for greater understanding of GnRH signalling with physiologically relevant stimulation paradigms and identifying new drugs that could be used for fertility control and the treatment of hormone-dependent cancer.”

The mathematical provides a novel insight into pulsatile GnRH signalling by showing how genuine frequency decoding could occur without the negative feedback thought to underlie. Since the signal architecture modeled is extremely common in cell signalling networks the finding may well have broad application to numerous systems.

This work also illustrates the potential value of collaboration between mathematicians and biomedical researchers. Dr Tsaneva-Atanasova and Professor McArdle are both core members of the University’s Predictive Life Sciences theme. Petros Mina, a project student working on an MSc programme in the Bristol Centre for Complexity Sciences, did the initial mathematical modeling. Most importantly, the mathematical modeling has provided not only novel mechanistic insight into the system, but also a series of testable hypotheses that form the basis of an ongoing MRC-funded project on GnRH pulse frequency decoding.

Explore further: Fertility treatment: Safer drug for women leads to same live birth rate

More information: Decoding GnRH neurohormone pulse frequency by convergent signalling modules by Krasimira Tsaneva-Atanasova, Petros Mina, Christopher J. Caunt, Stephen P. Armstrong and Craig A. McArdle, J. R. Soc. Interface published online 15 June 2011 doi: 10.1098/rsif.2011.0215.

Related Stories

Recommended for you

Flu study, on hold, yields new vaccine technology

September 2, 2015

Vaccines to protect against an avian influenza pandemic as well as seasonal flu may be mass produced more quickly and efficiently using technology described today by researchers at the University of Wisconsin-Madison in the ...

We've all got a blind spot, but it can be shrunk

August 31, 2015

You've probably never noticed, but the human eye includes an unavoidable blind spot. That's because the optic nerve that sends visual signals to the brain must pass through the retina, which creates a hole in that light-sensitive ...

Biologists identify mechanisms of embryonic wound repair

August 31, 2015

It's like something out of a science-fiction movie - time-lapse photography showing how wounds in embryos of fruit flies heal themselves. The images are not only real; they shed light on ways to improve wound recovery in ...

New 'Tissue Velcro' could help repair damaged hearts

August 28, 2015

Engineers at the University of Toronto just made assembling functional heart tissue as easy as fastening your shoes. The team has created a biocompatible scaffold that allows sheets of beating heart cells to snap together ...

Fertilization discovery: Do sperm wield tiny harpoons?

August 26, 2015

Could the sperm harpoon the egg to facilitate fertilization? That's the intriguing possibility raised by the University of Virginia School of Medicine's discovery that a protein within the head of the sperm forms spiky filaments, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.