Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice

Hosoda, Kiminori; Hammer, Robert E.; Richardson, James A.; Baynash, Amy Greenstein; Cheung, Jason C.; Giaid, Adel; Yanagisawa, Masashi

doi:10.1016/0092-8674(94)90017-5

Cited by 940 publications

(642 citation statements)

References 41 publications

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“…Recent studies suggest this difference might be at least partially explained by the expression of axon guidance molecules Slit and Robo on vagal NC (De Bellard et al, 2003). In contrast to our results, mice lacking members of the glial cell line-derived neurotrophic factor signaling pathway have enteric neurons in the anterior ENS (Cacalano et al, 1998;Pichel et al, 1996;Sanchez et al, 1996), whereas mutations in endothelin 3 or endothelin receptor type B cause the loss of ENS only in the distal colon Hosoda et al, 1994). In Phox2b -/-embryos, there is an initial migration of vagal NC into the proximal gut mesentery, but these progenitors are not maintained, leaving the entire gut without innervation (Pattyn et al, 1999).…”

Section: Nc Patterningcontrasting

confidence: 56%

Requirement for Foxd3 in the maintenance of neural crest progenitors

et al. 2008

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Understanding the molecular mechanisms of stem cell maintenance is crucial for the ultimate goal of manipulating stem cells for the treatment of disease. Foxd3 is required early in mouse embryogenesis; Foxd3 -/-embryos fail around the time of implantation, cells of the inner cell mass cannot be maintained in vitro, and blastocyst-derived stem cell lines cannot be established. Here, we report that Foxd3 is required for maintenance of the multipotent mammalian neural crest. Using tissue-specific deletion of Foxd3 in the neural crest, we show that Foxd3 flox/-; Wnt1-Cre mice die perinatally with a catastrophic loss of neural crest-derived structures. Cranial neural crest tissues are either missing or severely reduced in size, the peripheral nervous system consists of reduced dorsal root ganglia and cranial nerves, and the entire gastrointestinal tract is devoid of neural crest derivatives. These results demonstrate a global role for this transcriptional repressor in all aspects of neural crest maintenance along the anterior-posterior axis, and establish an unprecedented molecular link between multiple divergent progenitor lineages of the mammalian embryo.

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Section: Nc Patterningcontrasting

confidence: 56%

Requirement for Foxd3 in the maintenance of neural crest progenitors

et al. 2008

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“…Endothelin 1 was discovered in 1988 as vasoconstrictor by Yanagisawa et al (1988). Later, more members of this gene family were found and their functions annotated, so it is now evident that the endothelin system is involved in the formation of craniofacial structures, enteric ganglion neurons, pigmentation, and vasoconstriction in both mouse (Baynash et al 1994;Clouthier et al 1998;Hosoda et al 1994;Kurihara et al 1994;Ozeki et al 2004;Yanagisawa et al 1988) and zebrafish (Miller et al 2000;Parichy et al 2000). The active gene product of the endothelin genes is only 21 amino acids long and obtained via two steps of cleaving from the inactive precursors preproendothelin and big endothelin, respectively (Masaki 2004).…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of Two Endothelin Pathways in East African Cichlid Fishes

Diepeveen

Salzburger

2011

J Mol Evol

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The adaptive radiations of cichlid fishes in East Africa have been associated with the acquisition of evolutionary novelties as well as the ecological opportunities existing in the East African Great lakes. Two remarkable evolutionary innovations are the pharyngeal jaw apparatus, found in all cichlid species, and the anal fin egg-spots of mouthbrooding cichlids. Based on their conserved functions during the development of both the jaw apparatus and pigmentation, the endothelin ligands and receptors form a putative link between these naturally and sexually selected traits. Here we study the evolutionary history of four members of two endothelin pathways (Edn1/EdnrAa and Edn3b/EdnrB1a) to elucidate their possible roles during the evolution and development of key innovations in East African cichlids species. The analyses performed on partial sequences (ca. 6,000 bp per taxon) show that all four endothelin family members evolved under purifying selection, although both ligands are characterized by an accelerated rate of protein evolution in comparison to the receptors. In accordance with earlier findings, we show that the mature protein sequence of Edn1 and Edn3 are highly conserved, also in cichlids, whereas the preproendothelin parts are variable indicating relaxed selective constraints. In the receptors, nonsynonymous substitutions were mainly found in the ligand-binding domains suggesting functional divergence. Gene expression assays with Real-Time PCR indeed reveal that the two studied endothelin pathways are expressed in the cichlid pharyngeal jaw and in the haplochromine egg-spot (among other pigment-cell containing tissues), suggesting their involvement during morphogenesis of naturally and sexually selected traits in cichlids.

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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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Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice

Cited by 940 publications

References 41 publications

Requirement for Foxd3 in the maintenance of neural crest progenitors

Requirement for Foxd3 in the maintenance of neural crest progenitors

Molecular Characterization of Two Endothelin Pathways in East African Cichlid Fishes

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

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