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At least 19 recordsLinked to original sources
PubMed1991

Origins of the insect enteric nervous system: differentiation of the enteric ganglia from a neurogenic epithelium.

The enteric nervous system (ENS) of the moth Manduca sexta is organized into two distinct cellular domains: an anterior domain that includes several small ganglia on the surface of the foregut, and a more posterior domain consisting of a branching nerve plexus (the enteric plexus) that spans the foregut-midgut boundary. Previously, we showed that the neurons of the posterior domain, the enteric plexus, are generated from a large placode that invaginates from the caudal lip of the foregut; subsequently, the cells become distributed throughout the enteric plexus by a sequence of active migration. We now demonstrate that the neurons of the anterior domain, the cells of the enteric ganglia, arise via a distinct developmental sequence. Shortly after the foregut has begun to form, three neurogenic zones differentiate within the foregut epithelium and give rise to chains of cells that emerge onto the foregut surface. The three zones are not sites of active mitosis, as indicated by the absence of labelling with a thymidine analogue and by clonal analyses using intracellularly injected dyes. Rather, the zones serve as loci through which epithelial cells are recruited into a sequence of delamination and neuronal differentiation. As they emerge from the epithelium, the cells briefly become mitotically active, each cell dividing once or twice. In this manner, they resemble the midline precursor class of neural progenitors in the insect central nervous system more than neuroblast stem cells. The progeny of these zone-derived precursors then gradually coalesce into the ganglia and nerves of the anterior ENS. Although this reorganization results in some variability in the precise configuration of neurons within the ganglia, the overall morphology of the ganglia is highly stereotyped, consisting of cortical layers of cells that surround a ventral neuropil. In addition, a number of the neurons within the frontal and hypocerebral ganglia express identifiable phenotypes in a manner that is similar to many cells of the insect central nervous system. These observations indicate that the differentiation of the enteric ganglia in Manduca involves an unusual combination of features seen during the formation of other regions of the nervous system and, as such, constitutes a distinct program of neurogenesis.

Animals↗
PubMed1992

Roles of peptides in transmission in the enteric nervous system.

Studies of the enteric nervous system have proved to be important in the development of new concepts of the chemical nature of transmission from neurons. In particular, they have revealed the multiplicity of influences that peptides can have on transmission, such as their action as primary transmitters, and the fact that they often act as co-transmitters in enteric neurons. However, in other cases no roles can be attributed to neuropeptides in enteric neurons, and their involvement in short-term changes in excitability seems minor.

Animals↗
PubMed1992

Characterization of HNK-1 antigens during the formation of the avian enteric nervous system.

During vertebrate embryogenesis, interaction between neural crest cells and the enteric mesenchyme gives rise to the development of the enteric nervous system. In birds, monoclonal antibody HNK-1 is a marker for neural crest cells from the entire rostrocaudal axis. In this study, we aimed to characterize the HNK-1 carrying cells and antigen(s) during the formation of the enteric nervous system in the hindgut. Immunohistological findings showed that HNK-1-positive mesenchymal cells are present in the gut prior to neural crest cell colonization. After neural crest cell colonization this cell type cannot be visualized anymore with the HNK-1 antibody. We characterized the HNK-1 antigens that are present before and after neural crest cell colonization of the hindgut. Immunoblot analysis of plasma membranes from embryonic hindgut revealed a wide array of HNK-1-carrying glycoproteins. We found that two HNK-1 antigens are present in E4 hindgut prior to neural crest cell colonization and that the expression of these antigens disappears after neural crest colonization. These two membrane glycoproteins, G-42 and G-44, have relative molecular masses of 42,000 and 44,000, respectively, and they both have isoelectric points of 5.5 under reducing conditions. We suggest that these HNK-1 antigens and the HNK-1-positive mesenchymal cells have some role in the formation of the enteric nervous system.

Animals↗
PubMed1991

Vital dye labelling demonstrates a sacral neural crest contribution to the enteric nervous system of chick and mouse embryos.

We have used the vital dye, DiI, to analyze the contribution of sacral neural crest cells to the enteric nervous system in chick and mouse embryos. In order to label premigratory sacral neural crest cells selectively, DiI was injected into the lumen of the neural tube at the level of the hindlimb. In chick embryos, DiI injections made prior to stage 19 resulted in labelled cells in the gut, which had emerged from the neural tube adjacent to somites 29-37. In mouse embryos, neural crest cells emigrated from the sacral neural tube between E9 and E9.5. In both chick and mouse embryos, DiI-labelled cells were observed in the rostral half of the somitic sclerotome, around the dorsal aorta, in the mesentery surrounding the gut, as well as within the epithelium of the gut. Mouse embryos, however, contained consistently fewer labelled cells than chick embryos. DiI-labelled cells first were observed in the rostral and dorsal portion of the gut. Paralleling the maturation of the embryo, there was a rostral-to-caudal sequence in which neural crest cells populated the gut at the sacral level. In addition, neural crest cells appeared within the gut in a dorsal-to-ventral sequence, suggesting that the cells entered the gut dorsally and moved progressively ventrally. The present results resolve a long-standing discrepancy in the literature by demonstrating that sacral neural crest cells in both the chick and mouse contribute to the enteric nervous system in the postumbilical gut.

Animals↗
PubMed2026

Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development.

Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within families. SOX10 is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. Prior mapping of aganglionosis modifiers was achieved in a standard F1-intercross utilizing the Sox10Dom HSCR mouse model. Here we deploy a novel strategy of genotyping an extended pedigree pedigree of Sox10Dom mice on a mixed genetic background. GWAS in this pedigree points to novel aganglionosis modifier intervals with replication and refinement of prior modifier regions. Complementary omics analysis of the developing Enteric Nervous System (ENS) enabled identification of multiple high-priority candidate genes within these modifier intervals based on gene expression, chromatin accessibility, and presence of conserved SOX10 binding motifs. We implemented a prioritization pipeline for ranking potential modifiers that generated candidate lists including several well-known for effects on ENS development as well as multiple novel genes. Among the novel genes, Dach1 ranked as a top priority candidate gene for modifying migration of ENCDCs and thus influencing aganglionosis severity. The results identify genome intervals with intrinsic genes that are logical candidates for modifying Sox10Dom aganglionosis severity. We also note that several human orthologs to aganglionosis modifier candidate genes are within linkage disequilibrium blocks containing genetic variants associated with human gut motility disorders, which offers opportunity for gaining biological insight into human HSCR severity.

Animals↗
PubMed1991

Time of origin of neurons in the murine enteric nervous system: sequence in relation to phenotype.

The hypothesis was tested that developing enteric neurons withdraw from the cell cycle in a sequence related to their phenotype. The birthdays of immunocytochemically identified myenteric and submucosal neurons were determined in the murine duodenum and jejunum. [3H]thymidine ([3H]TdR) was injected into timed pregnant mice or pups at 4-8 hour intervals over a 24 hour period. Pups were killed on postnatal day 30 (P30). [3H]TdR incorporation was detected by radioautography in enteric neurons, which were phenotypically identified by the simultaneous detection of the immunoreactivities of 5-hydroxytryptamine (5-HT), choline acetyl transferase (ChAT), neuropeptide Y (NPY), enkephalin (ENK), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP). The dates of the earliest withdrawal from the cell cycle of neurons containing these markers were determined, as well as the length of time during which the identified neurons continued to be born, and the date on which their rate of birth was maximal. The birthdates of myenteric neurons that contained 5-HT (E8-E14, peak at E10) or ChAT (E8-E15, peak at E12) tended to be earlier than those that contained ENK (E10-E18, peak at E14), NPY (E10-E18, peak at E15), VIP (E10-P5, peak at E15), or CGRP (E10-P3, peak at E17). For any given immunocytochemically defined neuronal phenotype, submucosal neurons tended to be born later than their myenteric counterparts and submucosal neurons that contained neuropeptides were born later than those that contained only ChAT immunoreactivity. The day (E8) on which the first 5-HT- and ChAT-immunoreactive neurons became postmitotic is earlier than the day (E9) on which the colonization of the bowel by crest-derived cells has been detected. The population of neural precursors that colonizes the gut, therefore, is heterogeneous; many cells are proliferating, but a specific subset, which will ultimately give rise to serotoninergic or cholinergic neurons, is already postmitotic. Neurons continued to be born throughout fetal life and even after birth. Consequently, terminally differentiated neurons coexist in the developing enteric nervous system with dividing neural precursor cells. This observation is consistent with the idea that early developing neurons could affect the development of enteric neural precursors; moreover, they also demonstrate that it is possible to add neurons to the enteric plexuses even after the neural circuits on which the bowel depends have become functional.

Animals↗
PubMed1992

Functional morphology of the enteric nervous system with special reference to large mammals.

This short review reports the latest insights into the structural organization of the enteric nervous system, with special emphasis on the intrinsic innervation of the intestinal tract of large omnivorous mammals such as the pig. Using various techniques, including lesion experiments, morphological and neurochemical features of distinct neuronal populations as well as the direction of the axonal processes within the different nerve networks could be revealed. Special attention was paid to the considerable species differences in this respect between large omnivorous animals and humans on the one hand and small laboratory animals on the other hand.

Animals↗
PubMed1991

Congenital malformation of the enteric nervous system: history, immunohistodiagnosis and experimental approaches.

Hirschsprung's disease is characterized by the absence of enteric neurons from the distal colon and rectum. We reviewed the history of Hirschsprung's disease from its first description till the experimental approaches of its pathogenesis today. In our laboratory we introduced the use of monoclonal antibodies directed against neurofilament epitopes as useful tools in the diagnosis of Hirschsprung's disease and allied disorders. One particular monoclonal antibody (2FII) enables to distinguish between classical Hirschsprung's disease, long segment aganglionosis, hypoganglionosis, hyperganglionosis and chronic constipation. We also used monoclonal antibodies in experimental studies concerning the formation and malformation of the enteric nervous system in murine and chicken embryos. One particular antibody (HNK-I) was found to be a marker for very early precursors of enteric neurons in chicken (and human) embryos. In chicken embryos HNK-I visualizes cephalic neural crest cells, the area in the embryo that gives rise to all neurons in the gut. Using a microsurgical technique, we developed a model for Hirschsprung's disease in the chicken embryo.

Animals↗
PubMedDate not supplied

Localization of GTP-binding protein Go in the enteric nervous system in rat ileum.

The localization of a GTP-binding protein G(o) was examined immunohistochemically in rat ileum using antibodies against the alpha-subunit of G(o) (G(o) alpha). G(o) alpha-positive fibers clearly demonstrated the topography and structure of the enteric nervous system of the ileum. G(o) alpha was present only in the nervous system and was generally distributed both in synapse-rich and in nonsynaptic areas. The distribution of G(o) alpha in a nonsynaptic area suggests the possibility that G(o) may be involved not only in neurotransmission mechanisms but also in other functions.

Animals↗
PubMed1992

Immunohistochemistry for intermediate filaments in the enteric nervous system of the porcine small intestine.

Antibodies against the cytoskeletal neurofilament protein 200 and gliafilament acidic protein were used for an immunohistochemical staining of nerve and glia cells in porcine small intestine. In sections as well as in whole mount preparations, the morphological and topographical features of the enteric nerve plexus could be demonstrated. The enteric glia cells are characterized by an abundance of immunoreactive GFAP, which allows a subsequent staining of the plexus. NFP 200 is immunohistochemically recognized only in a part of the neurons. This immunoreactive neuronal population can be identified morphologically as Typ II-neurons, which are defined as adendritic and pseudouniaxonal to multiaxonal. The immunostaining of intermediate filaments is an easy and reproducible means for studying the enteric nervous system and invaluable for the histopathological diagnosis of its morphological abnormalities.

Animals↗
PubMed2026

Combined effects of Ret coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system.

Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in RET account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound RET enhancer (MCS+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigated the role of this enhancer by generating mice carrying a deletion of the orthologous Ret mcs+9.7 enhancer (Δmcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrated that enhancer deletion reduced Ret expression by 8% without altering ENS cell composition. However, reduced Ret expression was restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type-specific enhancer activity. To determine the functional consequences of further reducing Ret dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a Ret coding null allele (+/Δmcs+9.7;+/CFP). These mice exhibited additive reductions in Ret expression, altered Sox10 expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type-specific role for the mcs+9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by >50% loss of Ret function.

Journal Article↗
PubMed1992

A transgenic model for studying development of the enteric nervous system in normal and aganglionic mice.

The dopamine beta-hydroxylase promoter has been shown to direct expression of the reporter gene product, beta-galactosidase, to enteric neurons and putative embryonic neuroblasts in transgenic mice (Mercer et al., 1991; Kapur et al., 1991). In this paper, expression of the transgene, D beta H-nlacZ, in the gastrointestinal tract is characterized in more detail in wild-type mice and mice which are also homozygous for the lethal spotted allele (ls). Expression of the transgene in wild-type embryos was first detected in scattered mesenchymal cells in the proximal foregut on embryonic day 9.5, and progressed distally until embryonic day 13.5 when the entire length of the gut was colonized by such cells. Several observations suggest that the mesenchymal cells which express the transgene (MCET) are, in fact, enteric neuroblasts, probably derived from the vagal neural crest. (1) The presence of MCET in progressively more caudal portions of the embryonic gut correlated with the neurogenic potential of isolated gastrointestinal segments grafted under the renal capsule. (2) Mitotic activity of MCET was demonstrated by incorporation of [3H]thymidine in utero. (3) The migratory behavior of MCET and/or their precursors was revealed in anastomotic subcapsular grafts of gut from transgenic and non-transgenic embryos; enteric ganglia of the latter were populated by MCET from the former. (4) Enteric expression of the transgene postnatally was restricted to intrinsic neurons that coexpressed other phenotypic markers of neuronal differentiation. The pattern of transgene expression in ls/ls mice was identical to that seen in ls/+ and +/+ mice until embryonic day 12.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Microenvironmental factors in the normal and abnormal development of the enteric nervous system.

In order to gain insight into the molecular nature of some of the interactions that shape the ontogeny of the ENS, we have been studying two murine models in which enteric neural development is abnormal. One is the lethal spotted (ls/ls) mutant mouse. The other is a line of transgenic mice ("1975-2") that overexpress a homeobox-containing gene, Hox-1.4. Megacolon, an expansion of the bowel proximal to an abnormally innervated terminal gut, develops in each of these mice; however, the animals differ with respect to the nature of their neural defect. In ls/ls mice the terminal bowel is congenitally aganglionic (although hyperinnervated with nerve processes), because it cannot be colonized by migrating crest-derived cells. In contrast, the terminal gut of the transgenic (1975-2) mice contains ganglia, but the ultrastructure of these ganglia is that of peripheral, not enteric, nerve. On the basis of observations made thus far, we postulate that the ls/ls defect arises as a result of an overabundance and maldistribution of molecular components of basal laminae (such as laminin), which we have observed in the presumptive aganglionic bowel. We propose that crest-derived cells acquire a nerve-related laminin receptor when they enter the gut, which, when activated, induces these cells to withdraw from the cell cycle, differentiate, and extend neurites (or glial processes). Excessive laminin causes this response to occur prematurely. Cells that differentiate into neurons or glia presumably no longer migrate; therefore, the bowel distal to the region in which they respond to the abnormal extracellular ls/ls matrix does not become colonized by crest-derived cells. The molecular defect in the 1975-2 animals is unknown, but it would appear that it interferes, not with the migration of crest-derived cells, but with their subsequent differentiation along lineages appropriate to the bowel. Since the Hox-1.4 gene is overexpressed throughout the length of the gut, and not just in the abnormal section, we propose that prolonged exposure of neural precursors to cells that overexpress the Hox-1.4 gene product, renders the neural precursors unresponsive to the effects of the enteric microenvironment on neural differentiation. The abnormal zone of the 1975-2 bowel, therefore, is the region last to be colonized by crest-derived cells.

Animals↗
PubMed1992

Immunohistochemical and ultrastructural study of the enteric nervous system of earthworm, Lumbricus terrestris L.

Light and electronmicroscopic data reveal the presence of a well developed nerve plexus in the gut of the earthworm. The plexus contains subepithelial solitary nerve cells and fibers and an extensive neuropil among the muscle cells. There are two types of nerve cells in the enteric plexus. The first type contains mainly dense-core vesicles, and exhibits glyoxylic-acid induced fluorescence. Since none of these cells showed serotonin immunoreactivity, they are probably noradrenergic or dopaminergic. The second type contains large dense granules, suggesting that these cells are peptidergic (neurosecretory). A part of these cells are substance P immunoreactive, however no NPY, CGRP, or proctolin immunopositive cells were found. Ultrastructurally seven types of nerve fibers can be distinguished in the neuropil. Their distribution shows great variability within parts of the enteric canal. The observation that only two types of nerve cells are located within the gut makes it probable that some of the axons are extrinsic. According to immunohistological studies they may come from the stomatogastric system or from the segmental nerves. This is further supported by the fact that there is a well-developed subepithelial serotoninergic plexus in the fore-gut. Two types of neuromuscular junctions can be visualized in the muscular layer. The first type, representing a phylogenetically earlier form, exhibits wide junctional gap and pre- or postjunctional membrane thickening. The second type is the close contact. There are significantly more junctions observed in the fore-gut than in other parts of the gut.

Animals↗
PubMed1978

Properties of the enteric nervous system: limitation of access of intravascular macromolecules to the myenteric plexus and muscularis externa.

The possible presence of a blood-myenteric plexus barrier similar to the blood-nerve and blood-brain barriers was investigated. The myenteric plexus was found to be an enclosed tubular structure incompletely surrounded by a sheath of supporting cell processes. Capillaries do not enter the plexus. The capillaries which supply the myenteric layer differ in structure from capillaries of other layers of the gut and are non-fenestrated. Tracers, Evans blue labeled albumin or horseradish peroxidase, readily leak out of fenestrated capillaries, but do not readily escape from myenteric capillaries. These capillaries have impermeable junctions that prevent the passage of tracer between endothelial cells. A slow leakage of macromolecules is probably accounted for by transport through endothelial cells within plasmalemmal vesicles. A backup system of phagocytic cells removes this material and prevents the tracers leaking from the vasculature from reaching detectable concentrations in the extracellular space. Neither tracer was ever found in the myenteric plexus. Therefore, there is a blood-myenteric plexus barrier to macromolecules that resembles the blood-thymic barrier and may be functionally analogous to the blood-brain barrier.

Animals↗
PubMed1992

Oesophageal reflex responses: abnormalities of the enteric nervous system in patients with oesophageal symptoms.

An intraluminal balloon was used to study the peristaltic reflex, which is mediated by the intrinsic nerves of the oesophagus. Serial balloon distension was performed in nine asymptomatic volunteers and 133 patients with oesophageal symptoms. Eight of the volunteers had a normal response with proximal stimulation and distal inhibition of motility. Only 42 patients (31.6 per cent) had a normal response. The commonest abnormal response (39.1 per cent) was some form of failure of the distal inhibitory reflex. Other patterns of abnormality were an unresponsive oesophagus (15.8 per cent) with no motility change during balloon inflation, or spasm (13.5 per cent) proximal to the balloon. These alterations of secondary peristaltic activity suggest that there are abnormalities of the intrinsic (enteric) nerves of the oesophagus. Different abnormalities were found in patients with similar symptoms. Awareness of this difference might allow a more rational approach to treatment. This hypothesis was tested in a small pilot study treating functional dysphagia with cisapride. Three of nine patients had marked symptomatic improvement within 4 weeks and all three had an unresponsive oesophagus. The remaining six patients, who had failure of distal inhibition or a normal response, did not improve.

Adult↗