A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease

Puffenberger, Erik G.; Hosoda, Kiminori; Washington, Sarah S.; Nakao, Kazuwa; deWit, Damiane; Yanagisawa, Masashi; Chakravarti, Aravinda

doi:10.1016/0092-8674(94)90016-7

Cited by 845 publications

(501 citation statements)

References 43 publications

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“…Hirschsprung's disease is characterized by the congenital absence of the enteric ganglia from the hindgut. Mutations in the c-RET gene (22,24), the glial cell line-derived neurotrophic factor gene (49,50), the endothelin-3 gene (51), and the endothelin-B receptor gene (23) were identified in Hirschsprung's disease. Neuronal intestinal dysplasia is a human congenital disorder which is characterized by a megacolon with a normal number of ganglia or hyperplasia of enteric neurons (52,53).…”

Section: Discussionmentioning

confidence: 99%

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A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

Hatano¹,

Aoki²,

Dezawa³

et al. 1997

J. Clin. Invest.

112

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The Ncx/Hox11L.1 gene, a member of the Hox11 homeobox gene family, is mainly expressed in neural crest-derived tissues. To elucidate the role of Ncx/Hox11L.1, the gene has been inactivated in embryonic stem cells by homologous recombination. The homozygous mutant mice were viable. These mice developed megacolon with enteric ganglia by age 3-5 wk. Histochemical analysis of the ganglia revealed that the enteric neurons hyperinnervated in the narrow segment of megacolon. Some of these neuronal cells degenerated and neuronal cell death occurred in later stages. We propose that Ncx/Hox11L.1 is required for maintenance of proper functions of the enteric nervous system. These mutant mice can be used to elucidate a novel pathogenesis for human neuronal intestinal dysplasia. ( J. Clin. Invest. 1997. 100:795-801.)

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Section: Discussionmentioning

confidence: 99%

“…Mice lacking one of those gene products develop megacolon with the absence of enteric ganglia by perturbation of the migration (18,21). Human homologues of those genes are also responsible for the human congenital megacolon known as Hirschsprung's disease (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

Hatano¹,

Aoki²,

Dezawa³

et al. 1997

J. Clin. Invest.

112

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“…One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) 2,3 . The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon 4 .…”

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confidence: 99%

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

et al. 2004

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Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon 1 . One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) 2,3 . The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon 4 . In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR 5 , in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.Mice and individuals with HSCR with mutations in the EDNRB-mediated pathway have megacolon because of the absence of enteric neurons in the distal gut 1 . This regional specificity of aganglionosis could be explained by a temporal requirement for Ednrb between embryonic day (E) 11 and E12.5 (ref. 4), when vagal neural crest-derived ENS progenitors are populating the hindgut during mouse embryogenesis, such that in the absence of EDNRB the migratory wavefront is delayed near the ileocecal junction (Fig. 1a) [6][7][8] . To elucidate the molecular mechanisms for Ednrb expression in the ENS, we dissected the Ednrb genomic region. We isolated a 78-kb P1 genomic clone encompassing Ednrb (Fig. 1b) and used it to create four independent transgenic lines. When we crossed the individual transgenic lines into the Ednrb-null mice, all the lines rescued postnatal death from megacolon (Fig. 1c). Although three of the lines did not rescue the melanocyte defect in the Ednrb-null mice (Fig. 1c), one line (when homozygous with respect to the transgene) partially rescued the pigmentation defect that resembles the hypomorphic Ednrb s allele 9 (data not shown). These results suggested that the P1 clone contained the necessary information for expression of Ednrb in ENS progenitors. In addition, we mapped a main transcription start site Ednrb -/-Tg P5

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“…The breakthrough in deciphering the role of EDN3/EDNRB in NC development was the identification of the genetic defects responsible for the Piebald (s) and Lethal spotting (ls) mutations in mouse. These mutations reside in the genes encoding EDNRB (Puffenberger et al 1994) and its ligand EDN3, respectively (Greenstein-Baynash et al 1994).…”

Section: The Role Of Endothelin 3 In Neural Crest Cell Differentiationmentioning

confidence: 99%

The neural crest stem cells: control of neural crest cell fate and plasticity by endothelin-3

Dupin¹,

Real²,

LeDouarin³

2001

An. Acad. Bras. Ciênc.

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How the considerable diversity of neural crest (NC)-derived cell types arises in the vertebrate embryo has long been a key question in developmental biology. The pluripotency and plasticity of differentiation of the NC cell population has been fully documented and it is well-established that environmental cues play an important role in patterning the NC derivatives throughout the body. Over the past decade, in vivo and in vitro cellular approaches have unravelled the differentiation potentialities of single NC cells and led to the discovery of NC stem cells. Although it is clear that the final fate of individual cells is in agreement with their final position within the embryo, it has to be stressed that the NC cells that reach target sites are pluripotent and further restrictions occur only late in development. It is therefore a heterogenous collection of cells that is submitted to local environmental signals in the various NC-derived structures. Several factors were thus identified which favor the development of subsets of NC-derived cells in vitro. Moreover, the strategy of gene targeting in mouse has led at identifying new molecules able to control one or several aspects of NC cell differentiation in vivo. Endothelin peptides (and endothelin receptors) are among those. The conjunction of recent data obtained in mouse and avian embryos and reviewed here contributes to a better understanding of the action of the endothelin signaling pathway in the emergence and stability of NC-derived cell phenotypes.

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A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's disease

Cited by 845 publications

References 43 publications

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

A novel pathogenesis of megacolon in Ncx/Hox11L.1 deficient mice.

Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

The neural crest stem cells: control of neural crest cell fate and plasticity by endothelin-3

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