Conditional ablation of GFRα1 in postmigratory eneric neurons triggers unconventional neuronal death in the colon and causes Hirschsprungs's disease phenotype

Toshihiro Uesaka, Sanjay Jain, Shigenobu Yonemura, Yasuo Uchiyama, Jeffrey Milbrandt, Hideki Enomoto

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2171-2181
Number of pages11
JournalDevelopment
Volume134
Issue number11
DOIs
StatePublished - Jun 1 2007

Keywords

  • Enteric neuron
  • GDNF
  • GFRα1
  • Mouse

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