Science for Health
14 December 2012
Researchers at NIMR and UCL have used mathematical modelling to show how a network of genes can produce either spatial patterns or oscillations in developing tissues. The research is published in Journal of the Royal Society Interface.
The formation of complex tissues during embryonic development requires the accurate control of gene activity in order to produce the correct types of cells in the right place and at the right time. One strategy used by tissues to accomplish this takes advantage of oscillations to produce regular transitions in gene activity. A second strategy involves the use of secreted signals that switch genes on and off at different locations in the tissues to produce stripes of gene activity, a so-called multistate switch. Understanding how these mechanisms work is an important part of understanding tissue development.
In many tissues, groups of genes are involved that are connected together in networks so that each gene regulates the activity of some of the others. Jasmina Panovska-Griffiths working with Karen Page (Maths Department, UCL) and James Briscoe (pictured), from Developmental Biology at NIMR, looked at one such gene regulatory network, which they had previously shown to specify the spatial pattern of gene activity in the vertebrate neural tube. Despite comprising only four genes this network is complicated because it contains multiple cross-regulatory interactions that produce both positive and negative feedback, making it difficult to intuitively understand.
To overcome this, they used mathematical modelling to simulate the network and investigate how it functioned. The analysis revealed that the circuit appeared to be a natural way to construct a multistate switch out of gene interactions and that the circuit could readily be extended to produce more stripes of gene activity. They also found that small changes to how the genes regulated each other could make the circuit produce oscillations instead of stripes. This blurs the distinction between pattern-formation mechanisms that rely on temporal oscillations and those that produce stripes of activity. Because two distinct outputs were possible from the same gene network, the researchers called it the ‘AC/DC’ circuit.
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The AC/DC gene circuit, depicted, can generate either stripes of gene expression (top) or oscillations (bottom) depending on the relative strength of the negative feedback (red arrows) and positive feedback (green arrow).
The ease with which the behaviour of the AC/DC network can be changed to produce either stripes or oscillations raises the possibility that during evolution one of these types of mechanism has arisen from the other.
Karen Page, UCL
Understanding what generates patterns of gene activity in tissues is a key question in developmental biology. The complexity of the gene networks involved makes them difficult to analyse but our use of mathematical modelling is beginning to reveal new and unexpected details.
James Briscoe, NIMR
Jasmina Panovska-Griffiths, Karen M. Page and James Briscoe
A gene regulatory motif that generates oscillatory or multiway switch outputs
Journal of the Royal Society Interface 10(79):20120826. Fulltext.
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