Genes that control the connectivity of enteric neurons

11 March 2013

NIMR scientists have identified genes affecting enteric neuronal connectivity and a possible pathogenetic mechanism for disorders associated with abnormal intestinal motility. The research is published in Journal of Clinical Investigation.

The enteric nervous system (ENS) is the largest and most complex part of the peripheral nervous system and is composed of a vast network of interconnected ganglia embedded within the gut wall. Unlike all other parts of the peripheral nervous system, the ENS functions largely independently of the brain and spinal cord to control fundamental digestive functions. Developmentally, the ENS is derived from a relatively small population of vagal neural crest cells which expand to colonise the entire gut and differentiate into a plethora of neuronal subtypes and glial cells. Considerable recent progress has identified several molecular pathways that are critical for the development of enteric ganglia. However, the genetic and molecular mechanisms that underlie the assembly of functional neuronal circuits within the gut wall remain unknown. This is partly due to the lack of recognizable topographic organization of enteric neuron subtypes within the ganglia and the absence of predictive rules that correlate subtype identity to postsynaptic targets.

Several congenital and acquired disorders are known to be associated with clear anatomical deficits of enteric ganglia. Other conditions (such as intestinal pseudo-obstruction and irritable bowel syndrome), although frequently accompanied by debilitating intestinal dysmotility, lack any obvious pathology of the ENS and are thought to result from subtle changes in the connectivity of enteric neurons. Therefore, understanding the mechanisms that control ENS wiring is essential for discerning the broader role of the ENS in digestion and homeostasis and for exploring the pathogenetic mechanisms of congenital or acquired gastrointestinal motility disorders.

Valentina Sasselli and Werend Boesmans, working in the group of Vassilis Pachnis (pictured) in NIMR’s Division of Molecular Neurobiology, have shown that the planar cell polarity genes Celsr3 and Fzd3 control the growth and guidance of enteric neuron projections relative to the main axes of the gut. Genetic ablation of these genes disrupts the organization of neuronal projections, leading to relatively minor changes in the configuration of fibre tracts on the ENS but profound abnormalities of gastrointestinal motility.

These data demonstrate for the first time that modules of connectivity of enteric neurons established during embryogenesis underlie gastrointestinal function in adult animals and provide evidence that developmental deficits of the ENS contribute to the pathogenesis of idiopathic intestinal motility disorders.

Vassilis Pachnis

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Video recordings of distension-evoked motor patterns of control and Celsr3-deficient (Celsr3|Wnt1) colons analysed by spatiotemporal maps. The majority of mutant colons failed to generate efficient peristalsis and often showed tonic contractions aborally to the pellet (arrow in J).

Original article

Valentina Sasselli, Werend Boesmans, Pieter Vanden Berghe, Fadel Tissir, André M. Goffinet and Vassilis Pachnis (2013)

Planar cell polarity genes control the connectivity of enteric neurons

Journal of Clinical Investigation Epub ahead of print. Publisher abstract

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