Enteric Dopaminergic Neurons: Definition, Developmental Lineage, and Effects of Extrinsic Denervation

Abstract

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 Ͼ stomach or colon; proximal colon Ͼ 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 Ͼ Ͼ myenteric plexus; small intestine Ͼ stomach or colon). TH, DA, and DAT immunoreactivities were coincident in subsets of neurons (submucosal Ͼ 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.

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

“…S1), designated A12, A13, A14, and A15 groups in the hypothalamus, and A16 group in the olfactory bulb (25). DAergic neurons are also present in the enteric nervous system (26). FOXA1/2 are not expressed in enteric neurons, identified by expression of the panneuronal marker PGP9.5 (27), in the myenteric ganglia (Fig.…”

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

“…This is interesting, given the recently described distribution of dopamine neurons in the murine ENS, which suggests that dopamine neurons are more numerous in the proximal GI tract than the distal (Li, et al, 2004). It is possible that dopamine denervation has a more profound effect on the physiology and function of the lower GI tract than the upper precisely due to that proximal to distal gradient; greater reserve capacity might make upper GI function more resistant than lower GI function to similar degrees of dopaminergic denervation.…”

“…Tyrosine hydroxylase is a marker of catecholaminergic neurons, but adrenergic and noradrenergic inputs to the GI tract are largely extrinsic. Thus, the majority of TH-positive neurons with cell bodies in the myenteric plexus can be considered dopaminergic (Li, et al, 2004). Furthermore, ten days after the insult, the absence of TH-positive cell bodies most likely represents a loss of cells, rather than a mere downregulation of tyrosine hydroxylase (Jackson-Lewis, et al, 1995).…”

Physiological Modulation of Intestinal Motility by Enteric Dopaminergic Neurons and the D2Receptor: Analysis of Dopamine Receptor Expression, Location, Development, and Function in Wild-Type and Knock-Out Mice

“…The suggestion from these observations, that DA is an enteric neurotransmitter, has been confirmed recently. Enteric dopaminergic neurons, which express tyrosine hydroxylase (TH) and the dopamine transporter (DAT) but lack dopamine ␤-hydroxylase, have been identified in mouse, guinea pig (Li et al, 2004), and human (Anlauf et al, 2003).…”