Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system

Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Warren 1153, Boston, MA 02114, USA.
Developmental Biology (Impact Factor: 3.55). 06/2006; 293(1):203-17. DOI: 10.1016/j.ydbio.2006.01.032
Source: PubMed

ABSTRACT

Neural crest cells (NCC) migrate, proliferate, and differentiate within the wall of the gastrointestinal tract to give rise to the neurons and glial cells of the enteric nervous system (ENS). The intestinal microenvironment is critical in this process and endothelin-3 (ET3) is known to have an essential role. Mutations of this gene cause distal intestinal aganglionosis in rodents, but its mechanism of action is poorly understood. We find that inhibition of ET3 signaling in cultured avian intestine also leads to hindgut aganglionosis. The aim of this study was to determine the role of ET3 during formation of the avian hindgut ENS. To answer this question, we created chick-quail intestinal chimeras by transplanting preganglionic quail hindguts into the coelomic cavity of chick embryos. The quail grafts develop two ganglionated plexuses of differentiated neurons and glial cells originating entirely from the host neural crest. The presence of excess ET3 in the grafts results in a significant increase in ganglion cell number, while inhibition of endothelin receptor-B (EDNRB) leads to severe hypoganglionosis. The ET3-induced hyperganglionosis is associated with an increase in enteric crest cell proliferation. Using hindgut explants cultured in collagen gel, we find that ET3 also inhibits neuronal differentiation in the ENS. Finally, ET3, which is strongly expressed in the ceca, inhibits the chemoattraction of NCC to glial-derived neurotrophic factor (GDNF). Our results demonstrate multiple roles for ET3 signaling during ENS development in the avian hindgut, where it influences NCC proliferation, differentiation, and migration.

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    • "used because the epithelial anlagen of this organ develops at E8, later than the hindgut epithelium. To ensure epithelialmesenchymal adherence, recombinants were embedded into a three-dimensional collagen gel overnight (Fig. S3B) (Nagy and Goldstein, 2006a). Staining with QCPN confirms the quail origin of the mesenchyme (Fig. S3C). "
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    ABSTRACT: The enteric nervous system (ENS) develops from neural crest cells that migrate along the intestine, differentiate into neurons and glia, and pattern into two plexuses within the gut wall. Inductive interactions between epithelium and mesenchyme regulate gut development, but the influence of these interactions on ENS development is unknown. Epithelial-mesenchymal recombinations were constructed using avian hindgut mesenchyme and non-intestinal epithelium from the bursa of Fabricius. These recombinations led to abnormally large and ectopically positioned ganglia. We hypothesized that Sonic hedgehog (Shh), a secreted intestinal epithelial protein not expressed in the bursa, mediates this effect. Inhibition of Shh signaling, by addition of cyclopamine or a function-blocking antibody, resulted in large, ectopic ganglia adjacent to the epithelium. Shh overexpression, achieved in ovo using Shh-encoding retrovirus and in organ culture using recombinant protein, led to intestinal aganglionosis. Shh strongly induced the expression of versican and collagen type IX, whereas cyclopamine reduced expression of these chondroitin sulfate proteoglycans known to be inhibitory to neural crest cell migration. Shh also inhibited ENCC proliferation, promoted neuronal differentiation, and reduced expression of glial-derived neurotrophic factor, a key regulator of ENS formation. Ptc1 and Ptc2 were not expressed by ENCCs, and migration of isolated ENCCs was not inhibited by Shh protein. These results suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the composition of the intestinal microenvironment.
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    • "Between the caecum and the cloaca, the HNK1 antibody labeled all NCCs within the myenteric and submucosal plexuses as well as the avian-specific nerve of Remak on the dorsal side of the cloaca, derived from sacral NCCs (Fig. 1A) (Doyle et al., 2004; Nagy et al., 2012). Both plexuses also strongly expressed Ednrb mRNA (Fig. 1C,E) (Nataf et al., 1996; Nagy and Goldstein, 2006). Our strategy of pharmacological inhibition of ECE1 by phosphoramidon was expected to reduce the generation of mature endothelin peptides in the chick embryo, and consequently silence both EDNRA and EDNRB, which are required to build a normal craniofacial skeleton and establish a complete enteric nervous system, respectively. "
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    ABSTRACT: The enteric nervous system originates from neural crest cells that migrate in chains as they colonize the embryonic gut, eventually forming the myenteric and submucosal plexus. Failure of the neural crest cells to colonize the gut leads to aganglionosis in the terminal gut, a pathological condition called Hirschsprung disease (HSCR) in humans, also known as congenital megacolon or intestinal aganglionosis. One of the characteristics of the human HSCR is its variable penetrance, which may be attributable to the interaction between genetic factors, such as the endothelin-3/endothelin receptor B pathway, and non-genetic modulators, although the role of the latter has not well been established. We have created a novel HSCR model in the chick embryo allowing to test the ability of non-genetic modifiers to alter the HSCR phenotype. Chick embryos treated by phosphoramidon, which blocks the generation of endothelin-3, failed to develop enteric ganglia in the very distal bowel, characteristic of an HSCR-like phenotype. Administration of dexamethasone influenced the phenotype, suggesting that glucocorticoids may be environmental modulators of the penetrance of the aganglionosis in HSCR disease. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Apr 2015 · Biology Open
    • "Copyright © 2015 John Wiley & Sons, Ltd. JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE R E S E A R C H A RT I C L E Nagy and Goldstein, 2006; Reichenbach et al., 2008; Chalazonitis and Kessler, 2012 "

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