Conditional ablation of GFRalpha1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype.
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 GFRalpha1, 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 GFRalpha1 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 GFRalpha1 in the survival of enteric neurons and suggests that caspase-independent death can be triggered by abolition of neurotrophic signals.
Uesaka
Toshihiro
T
Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Jain
Sanjay
S
Yonemura
Shigenobu
S
Uchiyama
Yasuo
Y
Milbrandt
Jeffrey
J
Enomoto
Hideki
H
D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003106:Colon / Q000196:embryology / Q000294:innervation*; D017615:Enteric Nervous System / Q000196:embryology / Q000502:physiology* / Q000648:ultrastructure; D020868:Gene Silencing; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics*; D006627:Hirschsprung Disease / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D009841:Oligonucleotides / Q000235:genetics; D010641:Phenotype; D018709:Statistics, Nonparametric
C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009841:Oligonucleotides; D020169:Caspases