Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice
Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice
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DOI：
10.1172/jci34425
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Enomoto, Hideki
中科院分区：
文献类型：
--
作者：
Uesaka, Toshihiro;Nagashimada, Mayumi;Enomoto, Hideki
PET基因突变是先天性巨结肠症（HSCR）或先天性肠神经节细胞缺乏症的主要原因。然而，RET故障如何导致HSCR尚不清楚。最近显示，胶质细胞系衍生的神经营养因子（GDNF）家族受体α 1（GFR α 1）结合GDNF并激活RET，对于肠神经元的存活是必需的。在这项研究中，我们研究了Ret对肠神经元存活的调节及其在HSCR中的潜在参与。条件性消融迁移后肠神经元中的Ret引起结肠中广泛的神经元死亡，这导致结肠无神经节细胞症。为了进一步研究这一发现，我们通过降低Ret表达水平产生了HSCR的小鼠模型。这些小鼠概括了HSCR的遗传和表型特征，并由于肠神经嵴衍生细胞的迁移受损和连续死亡而发展为结肠无神经节细胞症。在结肠中也诱导肠神经元死亡，其中在肠神经嵴细胞迁移期后诱导Ret表达减少，表明减少的Ret表达直接影响结肠神经元的存活。因此，肠神经元存活对RET剂量敏感，并且细胞死亡可能参与HSCR的病因学。
Mutations in the PET gene are the primary cause of Hirschsprung disease (HSCR), or congenital intestinal aganglionosis. However, how RET malfunction leads to HSCR is not known. it has recently been shown that glial cell line-derived neurotrophic factor (GDNF) family receptor alpha 1 (GFR alpha 1), which binds to GDNF and activates RET, is essential for the survival of enteric neurons. In this study, we investigated Ret regulation of enteric neuron survival and its potential involvement in HSCR. Conditional ablation of Ret in postmigratory enteric neurons caused widespread neuronal death in the colon, which led to colonic aganglionosis. To further examine this finding, we generated a mouse model for HSCR by reducing Ret expression levels. These mice recapitulated the genetic and phenotypic features of HSCR and developed colonic aganglionosis due to impaired migration and successive death of enteric neural crest-derived cells. Death of enteric neurons was also induced in the colon, where reduction of Ret expression was induced after the period of enteric neural crest cell migration, indicating that diminished Ret expression directly affected the survival of colonic neurons. Thus, enteric neuron survival is sensitive to RET dosage, and cell death is potentially involved in the etiology of HSCR.