Signalling molecule insights could help repair damaged tissue or limit disease

02 April 2015

An image of the distribution of Shh protein in a cross-section of the developing spinal cord (Shh is stained white).

Image: An image of the distribution of Shh protein in a cross-section of the developing spinal cord (Shh is stained white).

A new study by researchers from the Francis Crick Institute and UCL (University College London) offers insight into how cells respond to the signalling protein Shh, a key factor in developing embryos and in some cancers.

Shh is a signalling protein that cells use to communicate with one another. It plays a vital role in embryo development and in the regeneration of damaged tissue, but, if unrestrained, it contributes to several types of cancer.

Different cells receive and respond to Shh in different ways. Understanding how these distinct responses arise could help design methods to either boost the regenerative potential of Shh or limit its detrimental effects.

A team of biologists led by James Briscoe at the Francis Crick Institute (currently based at Mill Hill Laboratories), carefully measured levels of Shh protein and the way cells responded to these different levels in the developing spinal cord, one of the embryonic tissues that depend on Shh.

Then, with physicists and mathematicians at UCL, they used the biological data to build and test computer simulations of the process. These simulations allowed the team to explore how signaling works and suggested three different mechanisms that cells use in response to Shh.

Experiments prompted by the simulations backed up the findings of the computer models and indicated that a combination of the three mechanisms is important in cells from the spinal cord. The computer simulations also highlighted modifications that were necessary to explain why the response to Shh is different in spinal cord cells than in other types of cell.

Chris Barnes, a physicist in the Department of Cell and Developmental Biology at UCL, said, "This so-called 'reverse-engineering' approach, which brings together quantitative biological data and powerful computational methods has helped us build and analyse a model of this really complex Shh system. It provides a great way to gain understanding and explore how biological processes work and it can provide insights, as in this case, that are difficult to acquire from experiments alone."

James Briscoe added: "This is an important step towards being able to predictably control the Shh triggered responses, for example in tissue engineering applications or in diseases where Shh activity is unchecked such as cancer.

"We were surprised to find different responses could be triggered by very small changes in the computational model. This could mean that the way cells respond to Shh is flexible and so relatively small changes or interventions could have significant effects. However there is much more to learn and we need to continue developing both the computational simulations and our biological understanding."

The paper, Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms, is published in Nature Communications.

  • An important signalling protein called Shh plays a role in repairing damaged tissue - but too much of it can result in cancer.
  • It's hoped that new insights into how Shh operates in different cells could lead to ways to harness the protein's potential for repairing damaged tissue or limit its disease-causing effect.
  • The study involved a collaboration between biologists at the Francis Crick Institute and physicists at UCL (University College London) and was funded in part by the Wellcome Trust.