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At least 19 recordsLinked to original sources
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↗
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↗
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↗
PubMed1978

[Effect of cholinergic substances on electrical processes in a ganglion of the enteric nervous system].

In the isolated in vitro segments of cat small intestine the sensitivity of myenteric neurons was studied by means of application of acetylcholine, nicotine, lobeline. The action of these drugs depended on their concentration: 10(-10)--10(-6)g/ml usually increased while larger concentrations (10(-5)g/ml) decreased the spontaneous activity. The preliminary application of d--tubocurarine (10(-6)g/ml), hexamethonium (10(-7)g/ml), and atropine (10(-6)g/ml) prevented the excitatory effects or suppressed neuronal discharges. The alteration of spontaneous activity seems to depend on the postsynaptic action of cholinergic drugs in M- and N-cholinoreceptors.

Acetylcholine↗
PubMed2024

Dynamic Pathology of Enteric Neural Network Using Curcumin-assisted Multiphoton Laser Imaging in Hirschsprung Disease.

BACKGROUND: In living tissue, it has been difficult to make microscopic-level observations without damaging the tissue. We have invented a novel intravital fluorescent observation method (IFOM) for real-time tissue observation, combining multiphoton laser scanning microscopy with curcumin vital staining (CVS-IFOM). The aim of this study was to use CVS-IFOM to analyze the enteric nervous system (ENS) in mice and human patients with hypoganglionosis and Hirschsprung disease (HSCR). METHODS: In an initial viability study, we compared live ENS images from nonfluorescent C57BL6 mice stained with curcumin (n = 5) and green fluorescent protein mice (n = 5) using multiphoton laser scanning microscopy. We then explored CVS-IFOM for the live examination of resected colon tissues from 1 patient with hypoganglionosis and 3 patients with HSCR. RESULTS: In the viability study, detailed ENS histologic features were only observed in the curcumin-stained mice. In the patient with hypoganglionosis, CVS-IFOM provided ENS details that were not visualized under hematoxylin and eosin staining or calretinin immunohistochemistry, allowing the analysis of ENS size, neural bundle number, and neural cell number per plexus. In patients with HSCR, CVS-IFOM showed a gradual hypoplastic change in the ENS from the oral edge to the anal edge, detecting disproportionate changes in the ENS within the same intestinal level, supporting a circumferentially uneven distribution of the intestinal ENS. CONCLUSIONS: CVS-IFOM may be supportive for intraoperative pathologic diagnosis during surgeries for HSCR.

Hirschsprung Disease↗
PubMed1979

Effect of intracerebroventricular administration of thyrotropin-releasing hormone upon the electroenteromyogram of rat duodenum.

Electroenteromyographic activity (EMG) of the duodenum was recorded in pentobarbital-anesthetized rats. TRH intraventricularly administered to rats produced changes in EMG such as increased amplitude, decreased frequency of slow waves and the association of bursts of spike potentials with nearly every cycle of the basal electric rhythm (BER). The effect was selectively prompt and marked in the EMG of proximal duodenum. The response was abolished by vagotomy or atropine injection and no response was elicited in the neonatally 6-OHDA-treated rat. Hypophysectomy, cord-transection or acute i.v. injection of 6-OHDA did not block the response. In the brain, TRH seems to stimulate the neuronal system controlling the vagus efferents involved in the regulation of the duodenal enteric nervous system which in turn modulates the myogenic excitability of the duodenum.

Animals↗
PubMed1979

Release of [3H]serotonin and its binding protein from enteric neurons.

The release of [3H]5-HT and its binding protein, SBP, from the guinea pig enteric nervous system was analyzed. Release of both [3H]5-HT and [3H]NE from strips of longitudinal muscle with adherent myenteric plexus preloaded with the respective radioactive amine was evoked by high K+ and the ionophore X537A. However, Ca2+-dependence could not be shown for [3H]5-HT release by either agent or for [3H]NE release by X537A. However, Ca2+-dependence (as well as inhibition of release by high Mg2+ and tetrodotoxin) could be demonstrated for the release of radioactivity evoked by electrical field stimulation of everted segments of ileum preloaded by perfusion through the serosal lumen with [3H]5-HT. Light and electron microscopic radioautography revealed that the sources of released radioactivity were axons, especially axonal varicosities containing a mixture of small clear and large dense-cored vesicles. SPB, but not the cytosol marker protein, lactic dehydrogenase, was spontaneously released from the perfused everted ileum. A marked increase in SBP (but not LDH) release was provoked by electrical field stimulation at 10 Hz, and this increased release (but not the spontaneous release) was Ca2+-dependent. It is concluded that SBP and 5-HT are probably stored together, at least in part in vesicles, and that both can be released by exocytosis from depolarized axon terminals.

Animals↗
PubMed1979

Does 5-hydroxytryptamine influence "purinergic" inhibitory neurons in the intestine?

Intrinsic inhibitory neurons to guinea pig taenia coli and small bowel circular muscle were activated by transmural electrical stimulation, and the postinhibitory contractile response of the muscle was utilized to evaluate whether or not the neuronal action of 5-hydroxytryptamine (5HT) was associated with the inhibitory neurons. The postinhibitory contractile responses of the small intestinal circular muscle were unaffected by 5HT. The 5HT antagonist methysergide also did not affect the poststimulus contractile response of the circular muscle. The amplitude and area under the contractile curve of the poststimulus contractile response of the taenia coli were reduced and the amplitude of the relaxation response to electrical stimulation was increased in one-half of the preparations after application of 5HT. Methysergide did not alter the poststimulus contractile response of the taenia coli. 5HT is implicated as a neurotransmitter substance for slow synaptic excitation within the enteric nervous system of the guinea pig small intestine; however, the 5HT synapses do not appear to be present on the "purinergic" inhibitory neurons nor on neurons that synaptically influence the inhibitory neurons.

Animals↗
PubMed2026

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Animals↗
PubMed2026

Glial Connexin-43 Is a Pathogenic Mechanism Promoting Gut Inflammation in Postoperative Ileus Induced by Gut Surgical Manipulation With Potential Relevance to Humans.

BACKGROUND & AIMS: Abdominal surgery often precipitates postoperative ileus (POI), a frequent and severe gastrointestinal (GI) motility disorder, through mechanisms that involve intestinal inflammation. Emerging data show that enteric glia acquire a reactive phenotype that aggravates POI, but how glia exert this effect remains unclear. Enteric glia express connexin-43 hemichannels (gCx43), which are implicated in neurological and inflammatory disorders. Thus, we aimed to decipher contributions of glial connexin-43 (Cx43) in the pathophysiology of POI. METHODS: We induced POI in mice using in vivo intestinal manipulation and used glial Cx43cKO (Sox10CreERT2;Cx43fl/fl) or RiboTag (Sox10CreERT2/Rpl22HA/+) mice to evaluate Cx43-dependent signaling. Human enteric glial cultures (hEGC) and muscularis externa obtained during intestinal surgery translated findings to patients. Transcriptome analysis, immunofluorescence co-labeling, Western blots, and Cx43 hemichannel activation were used for quantitative analysis. RESULTS: Cx43 is the highest expressed connexin in enteric glia in mice and humans. Up-regulation of Cx43 occurs in various disease models linked to POI, GI surgical trauma, inflammation, immune cell activation, and enteric gliosis. In the mouse POI model, glial Cx43-deletion reduces glial reactivity, pro-inflammatory signals, upregulates host protection genes, regulates immune cell activation, and prevents enteric neuropathy. In hEGCs, interleukin (IL)-1β induction opens Cx43 and stimulates release of IL-6 and C-C motif ligand 2 (CCL2). The Cx43 peptide inhibitor, 43Gap26, inhibits glial Cx43 activation, reduces IL-6 release, and blocks upregulation of macrophage activation factors and immune cell regulation factors. Surgical intestinal trauma in patients upregulates Cx43 during inflammation and enteric gliosis in mouse POI. CONCLUSIONS: Glial Cx43 signaling promotes enteric gliosis, immune cell activation, inflammation, and enteric neuropathy in mice with potential translatability to humans after intestinal surgical trauma and mechanical stress in POI. Interventions that block glial Cx43 activation may be protective against POI development.

Animals↗
PubMed1979

Studies on SK&F 29661, an organ-specific inhibitor of phenylethanolamine N-methyltransferase.

SK&F 29661 is an effective, reversible inhibitor of both central nervous system and adrenal phenylethanolamine N-methyl-transferase in vitro; its Ki values in our standard assay systems were 6 X 10(-7) M (central nervous system) and 3 X 10(-7) M (adrenal), respectively. In vivo, the drug inhibited the conversion of [3H]norepinephrine to [3H]epinephrine in the rat adrenal gland and upon chronic administration decreased the endogenous adrenal epinephrine/norepinephrine ratio in both the rat and squirrel monkey. SK&F 29661 did not, however, reduce rat brain stem PNMT activity after systemic administration; subsequent radioautographic studies indicated that the compound did not enter the central nervous system, presumably because of its high polarity. This drug may be useful in defining the physiological importance of peripheral phenylethanolamine N-methyltransferase inhibition.

Adrenal Glands↗
PubMedDate not supplied

The localization over time of exogenous aldosterone and angiotensin II in various organs.

Central nervous system effects have been demonstrated for angiotensin II and suggested for aldosterone. In order to determine whether either of these chemicals naturally crosses the blood-brain barrier, radioactive aldosterone and angiotensin II were introduced via intracardiac injections in rats. Samples of blood, liver, kidney, adrenals, cerebral cortex, and hypothalamus were collected at three, 15, and 60 minutes, frozen, dissolved, and counted. Blood levels for aldosterone and angiotensin II remained constant over 60 minutes. Aldosterone accumulated in the liver, kidney, adrenals and hypothalamus three minutes after injection, and levels diminished over time. Angiotensin II levels peaked in the adrenal, kidney, and liver after three minutes, and in the hypothalamus after 15 minutes. Cerebral cortex levels were lower than hypothalamic levels by 30% for aldosterone and 50% for angiotensin II. This suggests that both drugs may enter the central nervous system and selectively accumulate in the hypothalamus.

Adrenal Glands↗
PubMed1979

The distribution of carcinogens, 4-nitroquinoline-1-oxide and 4-hydroxyaminoquinoline-1-oxide, in the nervous system and its possible neurotoxicological significance.

4-NQO-14C can enter the grey matter parenchyma of the central nervous system of mice after i.v. injection. The level of its uptake by the central grey is higher than that taken up by the central white and by the trigeminal and spinal dorsal root ganglia. This pattern of distribution is strikingly different from that obtained after i.v. injection of 4-HAQO-14C, suggesting the possible occurrence of 4-NQO encephalomyelopathy having entirely different sites of lesions from those of 4-HAQO neuropathy.

4-Hydroxyaminoquinoline-1-oxide↗
PubMed1978

Cerebral localization of insulin by immunofluorescence.

An immunohistochemical procedure was used to detect cells which appear to bind insulin in the mouse brain. Strong fluorescence was observed in the cell bodies and processes of tanycytes lining the third ventricle and in the choroid plexi. These findings suggest that insulin enters the central nervous system, and indicate a route for its possible transport. This adds credence to earlier observations that the hypothalamic ependymal cells and processes form a highly organized and functional system, with different cells selectively absorbing (or sensing) particular substances from the systemic and ventricular circulations and transporting them (or information about them) to specific neuron receptors in the hypothalamus.

Animals↗
PubMed1979

Cholinergic stimulation of norepinephrine release in man. Evidence of a sympathetic postganglionic axonal lesion in diabetic adrenergic neuropathy.

Amplification of endogenous cholinergic activity-produced by the intravenous injection of edrophonium, an acetylcholinesterase inhibitor which does not enter the central nervous system, into normal subjects-resulted in significant and briefly sustained increments in the plasma concentrations of norepinephrine (153+/-15-234+/-29 pg/ml, P < 0.01) and epinephrine (16+/-3-34+/-5 pg/ml, P < 0.01) measured with a single-isotope derivative method. These increments were not attributable to reflex responses to hemodynamic changes and similar increments in plasma norepinephrine occurred in adrenalectomized (epinephrine deficient) patients. Thus, cholinergic activation results in direct stimulation of sympathetic postganglionic neurons, with augmented norepinephrine release, and of the adrenal medullae, with augmented epinephrine release, in man. Four diabetic patients with hypoadrenergic postural hypotension exhibited blunted sympathetic postganglionic neural responses, and normal adrenomedullary responses, to cholinergic stimulation (and to standing) indicative of the presence of a sympathetic postganglionic axonal lesion in diabetic adrenergic neuropathy. Nondiabetic patients with hypoadrenergic postural hypotension due to documented or probable central nervous system lesions exhibited normal responses to cholinergic stimulation produced in this fashion demonstrating the presence of intact sympathetic postganglionic neurons and adrenal medullae in these patients and providing further support for the conceptual soundness of this approach to the study of human adrenergic physiology and pathophysiology.

Adrenalectomy↗