Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Neurochem Int. 2012 Nov;61(6):839-47. doi: 10.1016/j.neuint.2012.01.028. Epub 2012 Feb 8.
This review discusses current knowledge about cell death in the developing enteric nervous system (ENS). It also includes findings about the molecular mechanisms by which such death is mediated. Additional consideration is given to trophic factors that contribute to survival of the precursors and neurons and glia of the ENS, as well to genes that, when mutated or deleted, trigger their death. Although further confirmation is needed, present observations support the view that enteric neural crest-derived precursor cells en route to the gut undergo substantial levels of apoptotic death, but that once these cells colonize the gut, there is relatively little death of precursor cells or of neurons and glia during the fetal period. There are also indications that normal neuron loss occurs in the ENS, but at times beyond the perinatal stage. Taken together, these findings suggest that ENS development is similar is some ways, but different in others from extra-enteric areas of the vertebrate central and peripheral nervous systems, in which large-scale apoptotic death of precursor neurons and glia occurs during the fetal and perinatal periods. Potential reasons for these differences are discussed such as a fetal enteric microenvironment that is especially rich in trophic support. In addition to the cell death that occurs during normal ENS development, this review discusses mechanisms of experimentally-induced ENS cell death, such as those that are associated with defective glial cell-line derived neurotrophic factor/Ret signaling, which are an animal model of human congenital megacolon (aganglionosis; Hirschsprung's disease). Such considerations underscore the importance of understanding cell death in the developing ENS, not just from a curiosity-driven point of view, but also because the pathophysiology behind many disorders of human gastrointestinal function may originate in abnormalities of the mechanisms that govern cell survival and death during ENS development.
这篇综述讨论了目前关于发育中肠神经系统（ENS）细胞死亡的知识。它还包括了关于介导这种死亡的分子机制的发现。此外，还考虑了促进 ENS 前体细胞和神经元及神经胶质存活的营养因子，以及那些突变或缺失会引发其死亡的基因。尽管还需要进一步的证实，但目前的观察结果支持这样一种观点，即进入肠道的肠神经嵴衍生前体细胞会经历大量的凋亡死亡，但一旦这些细胞定植在肠道中，在前胎儿期，前体细胞或神经元和神经胶质的死亡相对较少。也有迹象表明，正常的神经元丢失发生在 ENS 中，但在围产期之后。总之，这些发现表明 ENS 的发育在某些方面与脊椎动物中枢和周围神经系统的肠外区域相似，但在其他方面又有所不同，在这些区域中，前体细胞神经元和神经胶质在胎儿和围产期发生大规模的凋亡死亡。讨论了这些差异的潜在原因，例如富含营养支持的胎儿肠内微环境。除了在正常 ENS 发育过程中发生的细胞死亡外，本综述还讨论了实验诱导的 ENS 细胞死亡的机制，例如与胶质细胞衍生的神经营养因子/Ret 信号转导缺陷相关的细胞死亡，这是人类先天性巨结肠（无神经节细胞症；先天性巨结肠病）的动物模型。这些考虑强调了理解发育中 ENS 细胞死亡的重要性，不仅是出于好奇心，还因为许多人类胃肠道功能障碍的病理生理学可能起源于支配 ENS 发育过程中细胞存活和死亡的机制异常。
