Newgreen Donald, Young Heather M
Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, 3052, Victoria, Australia.
Pediatr Dev Pathol. 2002 May-Jun;5(3):224-47. doi: 10.1007/s10024-001-0142-y.
This review, which is presented in two parts, summarizes and synthesizes current views on the genetic, molecular, and cell biological underpinnings of the early embryonic phases of enteric nervous system (ENS) formation and its defects. In the first part, we describe the critical features of two principal abnormalities of ENS development: Hirschsprung's disease (HSCR) and intestinal neuronal dysplasia type B (INDB) in humans, and the similar abnormalities in animals. These represent the extremes of the diagnostic spectrum: HSCR has agreed and unequivocal diagnostic criteria, whereas the diagnosis and even existence of INDB as a clinical entity is highly controversial. The difficulties in diagnosis and treatment of both these conditions are discussed. We then review the genes now known which, when mutated or deleted, may cause defects of ENS development. Many of these genetic abnormalities in animal models give a phenotype similar or identical to HSCR, and were discovered by studies of humans and of mouse mutants with similar defects. The most important of these genes are those coding for molecules in the GDNF intercellular signaling system, and those coding for molecules in the ET-3 signaling system. However, a range of other genes for different signaling systems and for transcription factors also disturb ENS formation when they are deleted or mutated. In addition, a large proportion of HSCR cases have not been ascribed to the currently known genes, suggesting that additional genes for ENS development await discovery.
本综述分为两部分，总结并综合了目前关于肠神经系统（ENS）形成及其缺陷的早期胚胎阶段的遗传、分子和细胞生物学基础的观点。在第一部分中，我们描述了ENS发育的两种主要异常的关键特征：人类的先天性巨结肠症（HSCR）和B型肠道神经元发育异常（INDB），以及动物中的类似异常。这些代表了诊断范围的极端情况：HSCR有公认且明确的诊断标准，而INDB作为一种临床实体的诊断甚至存在都极具争议。讨论了这两种疾病在诊断和治疗方面的困难。然后，我们回顾了目前已知的基因，这些基因在发生突变或缺失时，可能会导致ENS发育缺陷。动物模型中的许多这些遗传异常表现出与HSCR相似或相同的表型，它们是通过对人类和具有类似缺陷的小鼠突变体的研究发现的。其中最重要的基因是那些编码GDNF细胞间信号系统中的分子的基因，以及那些编码ET-3信号系统中的分子的基因。然而，一系列用于不同信号系统和转录因子的其他基因在被删除或突变时也会干扰ENS的形成。此外，很大一部分HSCR病例尚未归因于目前已知的基因，这表明有待发现更多与ENS发育相关的基因。
