Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis
Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis
复制标题
DOI：
10.1172/jci69781
复制
发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Heuckeroth, Robert O.
中科院分区：
文献类型：
--
作者：
Lake, Jonathan I.;Tusheva, Olga A.;Heuckeroth, Robert O.
巨结肠疾病（HSCR）是一种部分渗透的少源性出生缺陷，发生在妊娠早期肠神经系统（ENS）前体未能定植远端肠道时。遗传缺陷是HSCR的基础，但出生缺陷的发生和严重程度的差异仍无法解释。我们假设非遗传因素可能有助于疾病的发展。在这里，我们发现斑马鱼筛选中发现的霉酚酸盐（一种新的鸟嘌呤核苷酸生物合成抑制剂）和其他8种药物会损害ENS的发展。在小鼠中，霉酚酸盐治疗选择性地损害ENS前体增殖，延迟前体迁移，并诱导肠神经节病。在2种不同的HSCR小鼠模型中，添加霉酚酸酯增加了hirschspron样病理的外显率和严重程度。霉酚酸盐处理也减少了ENS前体迁移以及培养的肠神经嵴来源细胞的板足形成、增殖和存活。利用嘌呤挽救基因Hprt的x失活嵌合体，我们发现ENS前体增殖减少最有可能导致霉酚酸诱导的迁移缺陷和神经节病。据我们所知，霉酚酸酯是第一种在哺乳动物模型中发现的导致主要ENS畸形和hirschsprung样病理的药物。这些研究表明，从头开始的鸟嘌呤核苷酸生物合成在ENS的发展中起着关键作用，并表明一些HSCR病例是可以预防的。
Hirschsprung disease (HSCR) is a partially penetrant oligogenic birth defect that occurs when enteric nervous system (ENS) precursors fail to colonize the distal bowel during early pregnancy. Genetic defects underlie HSCR, but much of the variability in the occurrence and severity of the birth defect remain unexplained. We hypothesized that nongenetic factors might contribute to disease development. Here we found that mycophenolate, an inhibitor of de novo guanine nucleotide biosynthesis, and 8 other drugs identified in a zebrafish screen impaired ENS development. In mice, mycophenolate treatment selectively impaired ENS precursor proliferation, delayed precursor migration, and induced bowel aganglionosis. In 2 different mouse models of HSCR, addition of mycophenolate increased the penetrance and severity of Hirschsprung-like pathology. Mycophenolate treatment also reduced ENS precursor migration as well as lamellipodia formation, proliferation, and survival in cultured enteric neural crest-derived cells. Using X-inactivation mosaicism for the purine salvage gene Hprt, we found that reduced ENS precursor proliferation most likely causes mycophenolate-induced migration defects and aganglionosis. To the best of our knowledge, mycophenolate is the first medicine identified that causes major ENS malformations and Hirschsprung-like pathology in a mammalian model. These studies demonstrate a critical role for de novo guanine nucleotide biosynthesis in ENS development and suggest that some cases of HSCR may be preventable.