Researchers have identified two genes that affect connectivity in the part of the nervous system that controls the function of the gastrointestinal tract. The team, from the Medical Research Council's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute), found a possible mechanism to explain why things go wrong in conditions where the gut muscles don't work properly, such as irritable bowel syndrome.
The peripheral nervous system generally connects the brain and spinal cord to the limbs and various organs throughout the body. The enteric nervous system is the largest and most complex part of the peripheral nervous system. It's made up of a vast network of interconnected nerve cells (neurons) that are embedded within the gut wall. These intricate neuronal circuits monitor the state of the gut and communicate with other organs to adjust its function to meet the constantly changing metabolic and physiological needs of the animal.
Improving knowledge of exactly how the enteric nervous system is wired is crucial to understanding a range of conditions known as intestinal motility disorders. For instance, some congenital and acquired conditions are associated with clear defects in the anatomy of the gut wall's nerve cell networks, including Hirschsprung disease, where babies are born with nerve cells absent in part or all of the large intestine, and Chagas disease, which is caused by a tropical parasite.
Other conditions, including irritable bowel syndrome and abdominal pseudo-obstruction (where patients have symptoms of an intestinal blockage but no obvious physical cause) are thought to be caused by subtle changes in the wiring of the enteric nervous system.
A lot of progress has been made recently in identifying molecular pathways that are critical for the development of these nerve cell networks in the gut wall. However, the genes and molecular mechanisms that underlie the assembly of circuits to carry out specific functions within these networks remain unknown. This is partly because there's a lack of recognisable organisation of nerve cell subtypes within the networks, and no rules to predict which subtypes interact with which target cells. The enteric nervous system is like a very complicated electrical circuit board, but no one knows which wires go where or do what.
The NIMR-led team investigated the development and organisation of the enteric nervous system in mice. They carried out a range of tests in the mice and in the laboratory, and bred mice with certain genes inactivated to look at the consequences.
They identified two genes known to play a role in 'planar cell polarity', or controlling cell growth in the right place and direction. These genes, called Celsr3 and Fzd3, were responsible for controlling and guiding the growth of the gut wall neurons relative to the main axes of the mouse gut. When these genes were inactivated in the mice, the scientists saw relatively minor changes in the configuration of the enteric nervous system, but profound abnormalities in intestinal motility (how well the gut muscles worked). This provided evidence that minor physiological abnormalities caused by genetic changes could have a large impact on intestinal motility and cause serious disorders.
The work was carried out by Valentina Sasselli and Werend Boesmans in the lab of Vassilis Pachnis at NIMR, along with colleagues from the Laboratory for Enteric Neuroscience in Leuven, Belgium and the Université Catholique de Louvain in Brussels, Belgium.
Dr Pachnis said: "Our results demonstrate for the first time that modules of connectivity of enteric neurons established during embryonic development underlie gastrointestinal function in adults. The findings also provide evidence that developmental deficits of the enteric nervous system are a cause of intestinal motility disorders."
The paper, Planar cell polarity genes control the connectivity of enteric neurons, was published in The Journal of Clinical Investigation.
