The regulated death of immature neurons, in response to the absence of neurotrophic factors, is crucial to the architecture of the developing nervous system. The enteric nervous system (ENS) regulates motility, secretion and blood flow in the gastrointestinal tract. However, unlike in other areas of the developing nervous system, neuronal apoptosis has not been detected, and survival signals that prevent it have yet to be identified. Jeffrey Milbrandt's and Hideki Enomoto's laboratories() now report that the survival of enteric neurons depends on GFRα1, a receptor for glial cell line-derived neurotrophic factor (GDNF). Using conditional GFRα1 mutant mice, the authors show that during late ENS development, GFRα1 inactivation induces the widespread death of enteric neurons in the distal gastrointestinal tract in a caspase-independent manner. Because Hirschsprung's disease in humans is associated with mutations in the RET receptor kinase - the signalling component of the GDNF receptor complex - it will be interesting to determine whether caspase-independent neuronal cell death underlies the etiology of this human condition.
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