Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease
Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease
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DOI：
10.1172/jci3702
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发表时间：
1998-09-15
影响因子：
15.9
通讯作者：
Yanagisawa, M
中科院分区：
文献类型：
--
作者：
Gariepy, CE;Williams, SC;Yanagisawa, M
斑点致死大鼠是先天性巨结肠病的一种自然发生的啮齿动物模型，其内皮素B受体（EDNRB）基因缺失，导致功能性EDNRB受体的表达消失。这种突变的纯合子大鼠（sl）表现出毛色斑点和先天性肠神经节细胞缺乏症。这些缺陷是由于神经嵴来源的表皮成黑素细胞和肠神经系统（ENS）前体分别完全定植在皮肤和肠中失败所致。我们证明，在正常大鼠发育过程中，EDNRB mRNA的表达模式是一致的表达ENS前体在整个肠道定植。我们使用人多巴胺-β-羟化酶（DPH）启动子来指导EDNRB的转基因表达以在sl/sl大鼠中定殖ENS前体。D β H-EDNRB转基因补偿了这些大鼠中缺乏的内源性EDNRB并防止了肠缺陷。转基因对毛色斑点没有影响，表明肠神经系统发育中EDNRB表达的关键时间开始于黑素细胞谱系与ENS谱系及其共同前体分离之后。转基因剂量影响先天性肠缺陷的发生率和严重程度，表明ENS发育中EDNRB激活下游的剂量依赖性事件。
The spotting lethal rat, a naturally occurring rodent model of Hirschsprung disease, carries a deletion in the endothelin-B receptor (EDNRB) gene that abrogates expression of functional EDNRB receptors. Rats homozygous for this mutation (sl) exhibit coat color spotting and congenital intestinal aganglionosis. These deficits result from failure of the neural crest-derived epidermal melanoblasts and enteric nervous system (ENS) precursors to completely colonize the skin and intestine, respectively. We demonstrate that during normal rat development, the EDNRB mRNA expression pattern is consistent with expression by ENS precursors throughout gut colonization. We used the human dopamine-beta-hydroxylase (DPH) promoter to direct transgenic expression of EDNRB to colonizing ENS precursors in the sl/sl rat. The D beta H-EDNRB transgene compensates for deficient endogenous EDNRB in these rats and prevents the intestinal defect. The transgene has no effect on coat color spotting, indicating the critical time for EDNRB expression in enteric nervous system development begins after separation of the melanocyte lineage from the ENS lineage and their common precursor. The transgene dosage affects both the incidence and severity of the congenital intestinal defect, suggesting dosage-dependent events downstream of EDNRB activation in ENS development.