Inhibition of in vitro enteric neuronal development by endothelin-3: mediation by endothelin B receptors

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1161-1173 ◽  
Author(s):  
J.J. Wu ◽  
J.X. Chen ◽  
T.P. Rothman ◽  
M.D. Gershon
Keyword(s):  
Smooth Muscle ◽  
Muscle Development ◽  
Neuronal Development ◽  
Enteric Neurons ◽  
Endothelin B ◽  
Endothelin 3 ◽  
Deficient Mice ◽  
Laminin Alpha1 ◽  
Do So

The terminal colon is aganglionic in mice lacking endothelin-3 or its receptor, endothelin B. To analyze the effects of endothelin-3/endothelin B on the differentiation of enteric neurons, E11-13 mouse gut was dissociated, and positive and negative immunoselection with antibodies to p75(NTR)were used to isolate neural crest- and non-crest-derived cells. mRNA encoding endothelin B was present in both the crest-and non-crest-derived cells, but that encoding preproendothelin-3 was detected only in the non-crest-derived population. The crest- and non-crest-derived cells were exposed in vitro to endothelin-3, IRL 1620 (an endothelin B agonist), and/or BQ 788 (an endothelin B antagonist). Neurons and glia developed only in cultures of crest-derived cells, and did so even when endothelin-3 was absent and BQ 788 was present. Endothelin-3 inhibited neuronal development, an effect that was mimicked by IRL 1620 and blocked by BQ 788. Endothelin-3 failed to stimulate the incorporation of [3H]thymidine or bromodeoxyuridine. Smooth muscle development in non-crest-derived cell cultures was promoted by endothelin-3 and inhibited by BQ 788. In contrast, transcription of laminin alpha1, a smooth muscle-derived promoter of neuronal development, was inhibited by endothelin-3, but promoted by BQ 788. Neurons did not develop in explants of the terminal bowel of E12 ls/ls (endothelin-3-deficient) mice, but could be induced to do so by endothelin-3 if a source of neural precursors was present. We suggest that endothelin-3/endothelin B normally prevents the premature differentiation of crest-derived precursors migrating to and within the fetal bowel, enabling the precursor population to persist long enough to finish colonizing the bowel.

BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis

2021 ◽  
Author(s):  
Natalia Bottasso Arias ◽  
Lauren Leesman ◽  
Kaulini Burra ◽  
John Snowball ◽  
Ronak M Shah ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Wnt Signaling ◽  
Rna Sequencing ◽  
Muscle Development ◽  
Target Genes ◽  
Bmp Signaling ◽  
Embryonic Mouse ◽  
Tracheal Cartilage ◽  
Cartilage Formation

Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

Neural regulation of intestinal smooth muscle growth in vitro

2000 ◽  
Vol 279 (3) ◽  
pp. G511-G519 ◽  
Author(s):  
M. G. Blennerhassett ◽  
S. Lourenssen
Keyword(s):  
Smooth Muscle ◽  
Sympathetic Neurons ◽  
Muscle Growth ◽  
Scorpion Venom ◽  
Enteric Neurons ◽  
Intestinal Smooth Muscle ◽  
Early Event ◽  
Thymidine Uptake

The loss of intrinsic neurons is an early event in inflammation of the rat intestine that precedes the growth of intestinal smooth muscle cells (ISMC). To study this relationship, we cocultured ISMC and myenteric plexus neurons from the rat small intestine and examined the effect of scorpion venom, a selective neurotoxin, on ISMC growth. By 5 days after neuronal ablation, ISMC number increased to 141 ± 13% ( n = 6) and the uptake of [3H]thymidine in response to mitogenic stimulation was nearly doubled. Atropine caused a dose-dependent increase in [3H]thymidine uptake in cocultures, suggesting the involvement of neural stimulation of cholinergic receptors in regulation of ISMC growth. In contrast, coculture of ISMC with sympathetic neurons increased [3H]thymidine uptake by 45–80%, which was sensitive to propranolol (30 μM) and was lost when the neurons were separated from ISMC by a permeable filter. Western blotting showed that coculture with myenteric neurons increased α-smooth muscle-specific actin nearly threefold to a level close to ISMC in vivo. Therefore, factors derived from enteric neurons maintain the phenotype of ISMC through suppression of the growth response, whereas catecholamines released by neurons extrinsic to the intestine may stimulate their growth. Thus inflammation-induced damage to intestinal innervation may initiate or modulate ISMC hyperplasia.

Neural regulation of in vitro giant contractions in the rat colon

2001 ◽  
Vol 281 (1) ◽  
pp. G275-G282 ◽  
Author(s):  
Asensio Gonzalez ◽  
Sushil K. Sarna
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Sch 23390 ◽  
Circular Muscle ◽  
Electrical Field Stimulation ◽  
Muscle Cells ◽  
Enteric Neurons ◽  
Rat Colon ◽  
Spontaneous Contractions

The rat middle colon spontaneously generates regularly occurring giant contractions (GCs) in vitro. We investigated the neurohumoral and intracellular regulation of these contractions in a standard muscle bath. cGMP content was measured in strips and single smooth muscle cells. The circular muscle strips generated spontaneous GCs. Their amplitude and frequency were significantly increased by tetrodotoxin (TTX), ω-conotoxin, N ω-nitro-l-arginine (l-NNA), and the dopamine D1 receptor antagonist Sch-23390. The GCs were unaffected by hexamethonium, atropine, and antagonists of serotonergic (5-HT1–4), histaminergic (H1–2), and tachykininergic (NK1–2) receptors but enhanced by NK3receptor antagonism. The guanylate cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ) also enhanced GCs to the same extent as TTX and l-NNA, and each of the three agents prevented the effects of the others. GCs were abolished by electrical field stimulation, S-nitroso- N-acetyl-penicillamine, and 8-bromo-cGMP. BAY-K-8644 and apamin enhanced the GCs, but they were abolished by D-600. Basal cGMP content in strips was decreased by TTX,l-NNA, or ODQ, but these treatments had no effect on cGMP content of enzymatically dissociated single smooth muscle cells. We conclude that spontaneous contractions in the rat colonic muscle strips are not generated by cholinergic, serotonergic, or histaminergic input. Constitutive release of nitric oxide from enteric neurons sustains cGMP synthesis in the colonic smooth muscle to suppress spontaneous in vitro GCs.

Possible role of gap junctions in activation of myometrium during parturition

1978 ◽  
Vol 235 (5) ◽  
pp. C168-C179 ◽  
Author(s):  
R. E. Garfield ◽  
S. M. Sims ◽  
M. S. Kannan ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Gap Junctions ◽  
Freeze Fracture ◽  
Normal Pregnancy ◽  
Pregnant Rats ◽  
Junction Formation ◽  
Synchronous Contraction ◽  
Do So

Gap junctions between smooth muscle cells of the myometrium of pregnant rats were found only immediately prior to, during and immediately after parturition by quantitative thin-section and freeze-fracture microscopy. Ovariectomy of 16- to 17-days-pregnant rats resulted in premature termination of pregnancy and the appearance of gap junctions. Methods that prolonged normal pregnancy in rats or maintained pregnancy in ovariectomized animals (progesterone treatment) prevented the appearance of gap junctions. Gap junctions formed in tissues incubated for 24--96 h in vitro without any hormonal influence. We propose that gap junctions are essential for normal labor and delivery for synchronous contraction of the muscle of the uterus. We present a model for control of parturition that may apply to other animals including humans. The model proposes: 1) the possible roles progesterone, prostaglandins, or estrogens may play in initiating gap-junction formation; 2) that the formation of gap junctions is a necessary step in activation of the myometrium leading to labor; and 3) that agents used to stimulate or inhibit labor may do so by affecting gap junctions.

scholarly journals II. Disorders of enteric neuronal development: insights from transgenic mice

1999 ◽  
Vol 277 (2) ◽  
pp. G262-G267 ◽  
Author(s):  
Michael D. Gershon
Keyword(s):  
Transgenic Mice ◽  
Neuronal Development ◽  
Congenital Defects ◽  
Precursor Pool ◽  
Neuronal Intestinal Dysplasia ◽  
Genes Encoding ◽  
Neuronal Precursors ◽  
Endothelin B ◽  
Intractable Problem ◽  
Endothelin 3

Understanding the development of congenital defects of the enteric nervous system, such as Hirschsprung’s disease, was, until recently, an intractable problem. The analysis of transgenic mice, however, has now led to the discovery of a number of genetic abnormalities that give rise to aganglionic congenital megacolon or neuronal intestinal dysplasia. The identification of the responsible genes has enabled the developmental actions of their protein products to be investigated, which, in turn, has made it possible to determine the causes of aganglionoses. Two models of pathogenesis have emerged. One, associated with mutations in genes encoding endothelin-3 or its receptor, endothelin B, posits the premature differentiation of migrating neural crest-derived progenitors, causing the precursor pool to become depleted before the bowel has been fully colonized. The second, associated with mutations in genes encoding glial cell line-derived neurotrophic factor (GDNF), its preferred receptor GFRα1, or their signaling component, Ret, appears to deprive a GDNF-dependent common progenitor of adequate support and/or mitogenic drive. In both cases, the terminal bowel becomes aganglionic when the number of colonizing neuronal precursors is inadequate.

Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons

Cell ◽  
1994 ◽  
Vol 79 (7) ◽  
pp. 1277-1285 ◽  
Author(s):  
Amy Greenstein Baynash ◽  
Kiminori Hosoda ◽  
Adel Giaid ◽  
James A. Richardson ◽  
Noriak Emoto ◽  
...  
Keyword(s):  
Enteric Neurons ◽  
Endothelin B Receptor ◽  
Endothelin B ◽  
Endothelin 3

scholarly journals Oxytocin regulates gastrointestinal motility, inflammation, macromolecular permeability, and mucosal maintenance in mice

2014 ◽  
Vol 307 (8) ◽  
pp. G848-G862 ◽  
Author(s):  
Martha G. Welch ◽  
Kara G. Margolis ◽  
Zhishan Li ◽  
Michael D. Gershon
Keyword(s):  
Neuronal Development ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Enteric Neurons ◽  
Developmentally Regulated ◽  
Mucosal Permeability ◽  
Myenteric Neurons ◽  
Neuronal Regulation ◽  
Macromolecular Permeability

Enteric neurons express oxytocin (OT); moreover, enteric neurons and enterocytes express developmentally regulated OT receptors (OTRs). Although OT (with secretin) opposes intestinal inflammation, physiological roles played by enteric OT/OTR signaling have not previously been determined. We tested hypotheses that OT/OTR signaling contributes to enteric nervous system (ENS)-related gastrointestinal (GI) physiology. GI functions and OT effects were compared in OTR-knockout (OTRKO) and wild-type (WT) mice. Stool mass and water content were greater in OTRKO mice than in WT. GI transit time in OTRKO animals was faster than in WT; OT inhibited in vitro generation of ENS-dependent colonic migrating motor complexes in WT but not in OTRKO mice. Myenteric neurons were hyperplastic in OTRKO animals, and mucosal exposure to cholera toxin (CTX) in vitro activated Fos in more myenteric neurons in OTRKO than WT than in WT mice; OT inhibited the CTX response in WT but not in OTRKO mice. Villi and crypts were shorter in OTRKO than in WT mice, and transit-amplifying cell proliferation in OTRKO crypts was deficient. Macromolecular intestinal permeability in OTRKO was greater than WT mice, and experimental colitis was more severe in OTRKO mice; moreover, OT protected WT animals from colitis. Observations suggest that OT/OTR signaling acts as a brake on intestinal motility, decreases mucosal activation of enteric neurons, and promotes enteric neuronal development and/or survival. It also regulates proliferation of crypt cells and mucosal permeability; moreover OT/OTR signaling is protective against inflammation. Oxytocinergic signaling thus appears to play an important role in multiple GI functions that are subject to neuronal regulation.

scholarly journals Defective smooth muscle development in qkI-deficient mice

2003 ◽  
Vol 45 (5-6) ◽  
pp. 449-462 ◽  
Author(s):  
Zhenghua Li ◽  
Nobuyuki Takakura ◽  
Yuichi Oike ◽  
Takanobu Imanaka ◽  
Kimi Araki ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Development ◽  
Deficient Mice
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