To clarify the role of Ret signaling components in enteric nervous system (ENS) 
development, we evaluated ENS anatomy and intestinal contractility in mice 
heterozygous for Ret, GFRalpha1 and Ret ligands. These analyses demonstrate that 
glial cell line-derived neurotrophic factor (GDNF) and neurturin are important 
for different aspects of ENS development. Neurturin is essential for maintaining 
the size of mature enteric neurons and the extent of neuronal projections, but 
does not influence enteric neuron number. GDNF availability determines enteric 
neuron number by controlling ENS precursor proliferation. However, we were 
unable to find evidence of programmed cell death in the wild type ENS by 
immunohistochemistry for activated caspase 3. In addition, enteric neuron number 
is normal in Bax(-/-) and Bid(-/-) mice, suggesting that, in contrast to most of 
the rest of the nervous system, programmed cell death is not important for 
determining enteric neuron numbers. Only mild reductions in neuron size and 
neuronal fiber counts occur in Ret(+/-) and Gfra1(+/-) mice. All of these 
heterozygous mice, however, have striking problems with intestinal contractility 
and neurotransmitter release, demonstrating that Ret signaling is critical for 
both ENS structure and function.