Conditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype

T Uesaka, S Jain, S Yonemura, Y Uchiyama… - 2007 - journals.biologists.com
T Uesaka, S Jain, S Yonemura, Y Uchiyama, J Milbrandt, H Enomoto
2007journals.biologists.com
The regulation of neuronal survival and death by neurotrophic factors plays a central role in
the sculpting of the nervous system, but the identity of survival signals for developing enteric
neurons remains obscure. We demonstrate here that conditional ablation of GFR α 1, the
high affinity receptor for GDNF, in mice during late gestation induces rapid and widespread
neuronal death in the colon, leading to colon aganglionosis reminiscent of Hirschsprung's
disease. Enteric neuron death induced by GFR α 1 inactivation is not associated with the …
The regulation of neuronal survival and death by neurotrophic factors plays a central role in the sculpting of the nervous system, but the identity of survival signals for developing enteric neurons remains obscure. We demonstrate here that conditional ablation of GFRα1,the high affinity receptor for GDNF, in mice during late gestation induces rapid and widespread neuronal death in the colon, leading to colon aganglionosis reminiscent of Hirschsprung's disease. Enteric neuron death induced by GFRα1 inactivation is not associated with the activation of common cell death executors, caspase-3 or -7, and lacks the morphological hallmarks of apoptosis, such as chromatin compaction and mitochondrial pathology. Consistent with these in vivo observations, neither caspase inhibition nor Bax deficiency blocks death of colon-derived enteric neurons induced by GDNF deprivation. This study reveals an essential role for GFRα1 in the survival of enteric neurons and suggests that caspase-independent death can be triggered by abolition of neurotrophic signals.
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