Li Z S, Pham T D, Tamir H, Chen J J, Gershon M D
Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
J Neurosci. 2004 Feb 11;24(6):1330-9. doi: 10.1523/JNEUROSCI.3982-03.2004.
The existence of enteric dopaminergic neurons has been suspected; however, the innervation of the gut by sympathetic nerves, in which dopamine (DA) is the norepinephrine precursor, complicates analyses of enteric DA. We now report that transcripts encoding tyrosine hydroxylase (TH) and the DA transporter (DAT) are present in the murine bowel (small intestine > stomach or colon; proximal colon > distal colon). Because sympathetic neurons are extrinsic, transcripts encoding TH and DAT in the bowel are probably derived from intrinsic neurons. TH protein was demonstrated immunocytochemically in neuronal perikarya (submucosal >> myenteric plexus; small intestine > stomach or colon). TH, DA, and DAT immunoreactivities were coincident in subsets of neurons (submucosal > myenteric) in guinea pig and mouse intestines in situ and in cultured guinea pig enteric ganglia. Surgical ablation of sympathetic nerves by extrinsic denervation of loops of the bowel did not affect DAT immunoreactivity but actually increased numbers of TH-immunoreactive neurons, expression of mRNA encoding TH and DAT, and enteric DOPAC (the specific dopamine metabolite). The fetal gut contains transiently catecholaminergic (TC) cells. TC cells are the proliferating crest-derived precursors of mature neurons that are not catecholaminergic and, thus, disappear after embryonic day (E) 14 (mouse) or E15 (rat). TC cells appear early in ontogeny, and their development/survival is dependent on mash-1 gene expression. In contrast, the intrinsic TH-expressing neurons of the murine bowel appear late (perinatally) and are mash-1 independent. We conclude that the enteric nervous system contains intrinsic dopaminergic neurons that arise from a mash-1-independent lineage of noncatecholaminergic precursors.
人们一直怀疑肠道中存在多巴胺能神经元；然而，由于交感神经对肠道的支配（其中多巴胺（DA）是去甲肾上腺素的前体），使得对肠道多巴胺的分析变得复杂。我们现在报告，编码酪氨酸羟化酶（TH）和多巴胺转运体（DAT）的转录本存在于小鼠肠道中（小肠>胃或结肠；近端结肠>远端结肠）。由于交感神经元是外源性的，肠道中编码TH和DAT的转录本可能来源于内在神经元。通过免疫细胞化学方法在神经元胞体中证实了TH蛋白的存在（黏膜下>>肌间神经丛；小肠>胃或结肠）。在豚鼠和小鼠肠道的原位以及培养的豚鼠肠神经节中，TH、DA和DAT免疫反应性在神经元亚群中是一致的（黏膜下>肌间）。通过对肠袢进行外源性去神经支配手术切除交感神经，并不影响DAT免疫反应性，但实际上增加了TH免疫反应性神经元的数量、编码TH和DAT的mRNA表达以及肠道中的DOPAC（特定的多巴胺代谢产物）。胎儿肠道含有短暂的儿茶酚胺能（TC）细胞。TC细胞是成熟神经元的增殖性神经嵴衍生前体，这些成熟神经元不是儿茶酚胺能的，因此在胚胎第14天（小鼠）或第15天（大鼠）后消失。TC细胞在个体发育早期出现，其发育/存活依赖于mash-1基因表达。相比之下，小鼠肠道中表达TH的内在神经元出现较晚（围产期），且不依赖于mash-1。我们得出结论，肠神经系统包含内在的多巴胺能神经元，它们起源于非儿茶酚胺能前体的mash-1非依赖性谱系。
