Disease relevance 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 [1].
• Phenotype variation in two-locus mouse models of Hirschsprung disease: tissue-specific interaction between Ret and Ednrb [2].
• Fourth, mice that are double heterozygous for loss-of-function mutations in Sox10 and Ednrb do not demonstrate synergistically increased hypopigmentation compared to mice that are single heterozygotes for either mutation alone, suggesting a lack of direct genetic interaction between these genes [3].
• 1. In the current study, the density and function of ETA and ETB receptors in mouse tracheal airway smooth muscle were determined over the time course of respiratory tract infection with influenza A/PR-8/34 virus [4].
• Virus-associated modulation of ETA and ETB receptor density and function was reversible with recovery from infection [4].

Psychiatry related information on Ednrb

• We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients [2].
• To determine the fate of Ednrb-expressing cells during this critical period, we generated a strain of mice with the bacterial beta-galactosidase (lacZ) gene inserted downstream of the endogenous Ednrb promoter [5].

High impact information on Ednrb

• 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 [1].
• In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb [1].
• One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB) [1].
• Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease [6].
• These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes [7].

Chemical compound and disease context of Ednrb

• The i.pl. administration of the selective ETA antagonist BQ-123 (1-10 nmol) antagonized the thermal hyperalgesia detected by the unilateral hot plate test, observed in both inflammatory models, whereas the i.pl. administration of the ETB selective antagonist BQ-788 (17.7 nmol) failed to modify this [8].

Biological context of Ednrb

• To determine when EDNRB signalling is required during embryogenesis, we have exploited the tetracycline-inducible system to generate strains of mice in which the endogenous Ednrb locus is under the control of the tetracycline-dependant transactivators tTa or rtTA [9].
• Consistent with this, neither Ednrb nor Edn3 mRNA was detected in 3/3 tested immortal lines of mouse melanoblasts and 5/5 lines of melanocytes, of various genotypes [10].
• However, it is hard to assess cell differentiation in these mixed cultures, and it is not known whether Ednrb has any role in the postnatal melanocytic lineage [10].
• Mutation analysis revealed that their Ednrb lacked 318 nucleotides encoding Ednrb transmembrane domains owing to deletion of exons 2 and 3 [11].
• A genome wide scan confirmed the presence of a QTL (peak LOD = 6.4) on chromosome 14 near the piebald (Ednrb) and 5-hydroxytryptamine(2A) (Htr2a) loci [12].

Anatomical context of Ednrb

• The results suggest that Ednrb plays a significant role during melanocyte differentiation and effects melanocyte development by both cell non-autonomous and cell-autonomous signaling mechanisms [13].
• The endothelin receptor B gene (Ednrb) encodes a G-protein-coupled receptor that is expressed in a variety of cell types and is specifically required for the development of neural crest-derived melanocytes and enteric ganglia [13].
• By comparing Ednrb(lacZ)/+ and Ednrb(lacZ)/Ednrb(lacZ) embryos, we determined that the Ednrb pathway is not required for the initial specification and dispersal of melanoblasts and ENS precursors from the neural crest progenitors [5].
• 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype [14].
• Quail Ednrb is expressed in NCCs migrating along the ventral pathway, which gives rise to the peripheral nervous system, including enteric ganglia [15].

Associations of Ednrb with chemical compounds

• The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription [16].
• Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control [16].
• Ednrb27Pub mice harbor a mutation at a critical proline residue in the fifth transmembrane domain of the EDNRB protein [17].
• The nonselective ETA/ETB receptor antagonist PD 142893 blocked both ET and S6c-induced enhancement of the PTH responses [18].
• The antagonists used were BQ-123, an ETA antagonist, BQ-788, an ETB antagonist, and SB209670, an ET(A&B) antagonist [19].

Physical interactions of Ednrb

• The development of melanocytes from neural crest-derived precursor cells depends on signaling by the receptor tyrosine kinase KIT and the G protein-coupled endothelin receptor B (EDNRB) pathways [20].

Other interactions of Ednrb

• The requirement for SOX10 and endothelin-3/EDNRB signalling pathway during enteric nervous system (ENS) and melanocyte development, as well as their alterations in Waardenburg-Hirschsprung disease (hypopigmentation, deafness and absence of enteric ganglia) are well established [21].
• Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development [21].
• Endothelin (ET)-1 is one of the most potent agonists of airway smooth muscle and can act via two different ET receptor subtypes, i.e., ETA and ETB [22].
• The first inner loop of endothelin receptor type B is necessary for specific coupling to Galpha 13 [23].
• The mRNA expressions for ET-1 and ETB receptor were up- and down-regulated, respectively, by IL-1beta [24].

Analytical, diagnostic and therapeutic context of Ednrb

• Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb [2].
• To address the question of whether melanocyte development depends entirely on a cell-autonomous action of Ednrb, we performed a series of tissue recombination experiments in vitro, using neural crest cell cultures from mouse embryos carrying a novel Ednrb-null allele characterized by the insertion of a lacZ marker gene [13].
• Using confocal double immunofluorescence, we have observed that ET-A seems to be localized in bipolar cell dendrites, whereas ET-B is localized in horizontal cells [25].
• Nevertheless, in this animal model of ETB receptor deficiency, endothelial function is impaired independent of salt-enriched diet or hypertension [26].
• The expression of ETB receptor mRNAs in Bergmann glial cells was revealed by single-cell RT-PCR [27].

References