Conditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype
Conditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype
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DOI：
10.1242/dev.001388
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发表时间：
2007-06-01
期刊：
影响因子：
4.6
通讯作者：
Enomoto, Hideki
中科院分区：
文献类型：
--
作者：
Uesaka, Toshihiro;Jain, Sanjay;Enomoto, Hideki
神经营养因子对神经元存活和死亡的调节在神经系统的塑造中起着核心作用，但发育中的肠神经元的存活信号的身份仍然不清楚。我们在这里证明，有条件的消融GFR α 1，GDNF的高亲和力受体，在小鼠妊娠晚期诱导快速和广泛的结肠神经元死亡，导致结肠无神经节细胞症联想到先天性巨结肠症。由GFR α 1失活诱导的肠神经元死亡与常见细胞死亡执行器caspase-3或-7的激活无关，并且缺乏凋亡的形态学标志，如染色质致密化和线粒体病理学。与这些体内观察结果一致，无论是半胱天冬酶抑制还是Bax缺乏都不能阻断GDNF剥夺诱导的结肠源性肠神经元死亡。这项研究揭示了GFR α 1在肠神经元存活中的重要作用，并表明半胱天冬酶非依赖性死亡可以通过消除神经营养信号来触发。
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 alpha 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 alpha 1 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 GFR alpha 1 in the survival of enteric neurons and suggests that caspase- independent death can be triggered by abolition of neurotrophic signals.