Wednesday, 21 May 2014

A divorce in development: single regulators can raise arteries alone

Image Source: Serial/Trash
Understanding how blood vessels are born and propagated is vital for the treatment of a whole host of diseases including heart disorders, diabetes and cancer. Scientists from Oxford’s Ludwig Institute for Cancer Research have begun to reveal the mechanism by which the switching on of specific genes leads to the development of arteries. 

A vast network of blood-carrying arteries feeds our body with the oxygen and nutrients it needs to survive. Within a young embryo, this network takes its primitive shape in a series of stages. First, the cell type which will later make up the inner-walls of all blood vessels, the endothelial cells, is generated. Then simple tube-like structures of these endothelial cells must differentiate into either arteries or veins.

But the story doesn’t end there – the process of sprouting new blood vessels continues throughout life and indeed maintaining just the right distribution is critical to our health. Too few, too many or abnormally-developed blood vessels can all lead to disease. Interestingly, although cancer and Alzheimer’s disease are very different conditions, scientists believe that the underlying molecular processes responsible for the defective blood vessel development that comes with them are very similar and therefore exciting targets for research.

All aspects of our development, from the formation of vital organs within the embryo to the healing of wounds in adulthood, utilise similar molecular tools to lay down the pattern which governs how cells and tissues specialise into one of many types – rather like a blueprint. External signalling molecules are deployed to pass instructions to cells depending on where they lie in the overall blueprint. These signals can be sensed by each cell individually via receptor molecules protruding from their surface.

Scientists are confident of the signalling molecules released during artery development. Vascular Endothelial Growth Factor (VEGF) spreads diffusely across tissues and is the primary driver of general blood vessel formation. The Notch pathway, which operates when adjacent cells touch, is implicated in deciding which vessels become arteries. However, signalling messages are short lived – how does an artery know to remain an artery? It is this last link in the chain that until now scientists have been most unsure about – how can several signalling pathways be combined inside the cell so that the correct genes are turned on for operating an artery?

All cells carry a copy of the entire genome, but few genes are required in every cell or all the time. Genes lie adjacent to ‘enhancers’, DNA sequence elements that do not encode protein but rather allow control of when, where and how fast a gene is read. Such control is governed by DNA-binding proteins, which sit on the DNA structure and interact with the gene-reading machinery.

Image Source: Shutterstock Copyright: Crystal Eye Studio

Dr Sarah De Val and her colleagues at Oxford have conducted a series of experiments in mice and zebrafish that reveal which DNA-binding proteins are important in the formation of arteries. They first pinpointed which enhancers are most important for the activation of an artery-specific Notch gene before demonstrating which of the known DNA-binding proteins engage them. These included a DNA-binding component of the Notch pathway and three members of the SOX-gene family, utilised during development throughout the animal kingdom.

By fusing copies of the artery enhancers to a bacterial gene that produces a bright blue protein when activated, it was possible for the researchers to trace the pattern of artery formation at different stages during embryo development. Unsurprisingly, when they cut out the binding sites at which the proteins responsible for formation of endothelial cells associate with enhancer DNA, or chemically disabled the VEGF signalling pathway, the normal pattern of Notch gene activation was completely lost. But intriguingly, deleting the binding sites for the SOX and Notch proteins only had a severe effect when carried out in parallel – loss of regulation by either SOX or Notch individually was of little importance.

This finding was echoed by injecting inhibitory DNA molecules into embryos to simultaneously turn off the genes encoding the DNA-binding SOX and Notch proteins. Although endothelial cells were able to form a network of primitive blood vessels, the principle artery, the aorta, was missing and none of the known genes common to arteries were activated.

As a general rule, developmental characteristics tend to emerge in cells located in regions where two or more necessary signals overlap. This research, proclaiming that proteins of either the SOX or Notch pathways alone are sufficient for much of artery function without the other, intriguingly contradicts this.

Highlighting the fact that the vascular system is extremely sensitive to genetic fine-tuning, Dr De Val’s study reveals some of the first molecular targets for potential vascular disease therapies. At the same time, it exposes some unusual molecular intricacies that will continue to excite scientists for some time.

This summary by Christopher Waite was shortlisted for Access to Understanding 2014 and was commended by the judges. It describes research published in the following article, selected for inclusion in the competition by the British Heart Foundation:

PMCID: PMC3718163
N. Sacilotto, R. Monteiro, M. Fritzsche, P.W. Becker, L. Sanchez-del-Campo, K. Liu, P. Pinheiro, I. Ratnayaka, B. Davies, C.R. Goding, R. Patient, G. Bou-Charios & S. De Val.
Proceedings of the National Academy of Science USA (2013) 110(29), 11893-11898.

Access to Understanding entrants are asked to write a plain English summary of a research article. For Access to Understanding 2014 there were 10 articles to choose from, selected by the Europe PMC fundersThe articles are all available from Europe PMC, are free to read and download, and were supported by one or more of the Europe PMC funders.

Look out here and on Twitter @EuropePMC_news for further competition news and other Europe PMC announcements.    

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