Open AccessConditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype
Author(s) -
Toshihiro Uesaka,
Sanjay Jain,
Shigenobu Yonemura,
Yasuo Uchiyama,
Jeffrey Milbrandt,
Hideki Enomoto
Publication year - 2007
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.001388
Subject(s) - biology , enteric nervous system , glial cell line derived neurotrophic factor , neurotrophic factors , programmed cell death , neurotrophin , microbiology and biotechnology , cancer research , apoptosis , neuroscience , immunology , receptor , genetics
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.