ABSTRACT

During development, the gut is colonised by three populations of neuronal progenitors originating in the rostral truncal, vagal and sacral regions of the neural crest. Knockout of the mash-1 transcription factor leads to a complete lack of enteric ganglia in the oesophagus, by blocking colonisation by rostral truncal neural crest cells. In the rest of the gut, there is a selective loss of mash-1-sensitive serotonergic nerve cells but other cell types, for example those containing CGRP, are apparently unaffected. In contrast, knockout of GDNF, or its receptor, Ret, prevents enteric innervation of the entire gut below the oesophagus and forestomach. The neurotrophin, NT-3, also influences enteric neuronal development, at least in part by interacting with an unidentified cytokine that activates the CNTF receptorα. A localised aganglionosis of the distal colon occurs in mice lacking functional endothelin-3 or its receptor ETB. This may be due to an overproduction of the α subunit of Laminin-1 in this region, which promotes premature differentiation and failure to colonise by neuronal precursors. Hirschsprung’s disease in humans is sometimes associated with mutations of RET, ETB and ET-3, but other mechanisms are also likely to contribute. It is likely that the existence and causes of more subtle enteric neuropathies will become apparent as our understanding of enteric neuronal development continues to grow.