Modeling Development and Disease in the Enteric Nervous System

The enteric nervous system (ENS) in our gastrointestinal tract is responsible for normal gut function, including peristaltic contraction. Embryonic development of the ENS involves the colonization of the gut wall from one end to the other by a population of proliferating neural crest (NC) cells. Failure of these cells to invade the whole gut results in the relatively common, potentially fatal condition known as Hirschsprung disease (HSCR). Probabilistic cellular automata (CA) models' provide insight into the colonization process. At the population level, the results exhibit an organised colonization wave, which extends through frontal expansion. Under a certain range of proliferation probabilities, the success or failure of colonization in the CA models is not certain, but probabilistic. At the individual level, a full exploration of agent progeny provides insight into a highly unequal clonal contributions. The CA models generated experimentally testable predictions, which have subsequently been confirmed. The model results imply that HSCR is chiefly a NC cell proliferation defect and not, as previously thought, a NC cell motility defect. The phenomenon of incomplete penetrance seen in a number of birth defects including HSCR, where possession of a dominant causative mutation does not ensure the defect, is also explained by the CA results.