Differential expression of EDN3 in cancer of the vulva.

In these brief notes we document work using published microarray data (1, 2) to pioneer integrative transcriptome analysis comparing vulvar carcinoma to its tissue of origin, the vulva. We report the differential expression of endothelin 3, encoded by EDN3, in cancer of the vulva. EDN3 may be of pertinence to understanding transformation and disease progression in vulvar cancer (3).

Genetics of skin color in chickens

The phenotypic diversity of skin color in wild and domestic animals is an important characteristic for biologists and breeders. The color of the skin can be a sign of the breed. Some people prefer a bird with a dark skin color; such meat is considered more delicious and nutritious. In European countries, yellow-skinned or white-skinned birds are preferred.The variety of skin colors depends on a combination of specific genes that affect the deposition of xanthophylls and melanins, polygenic modifiers, and environmental factors. The yellow color of the egg yolk, as well as the white or yellow color of the skin and fat, is caused by carotenoids and xanthophylls. The dark colors of the skin and feathers depend on melanin, which is divided into eumelanin - the black pigment of the eyes, plumage, connective tissue and skin, and pheomelanin, which determines the brown shades of the plumage.Even in the last century, the Mendelian inheritance of white and yellow skin color in chickens was studied and the autosomal genes (W, w) that cause it were determined. Later in 2008, associations of the W locus with the beta-carotene dioxygenase 2 (BCDO2) gene were found. The results of these studies also changed earlier ideas about the origin of domestic chicken.Studies of the genetics of dark skin color were conducted on hyperpigmented silk breed of chickens. Classical breeding experiments have determined that this trait is controlled by two interacting genes: a sex-linked cutaneous melanin inhibitor (Id) and autosomal fibromelanosis (Fm).In 2010, the Fm gene that causes skin tissue hyperpigmentation was associated with the endothelin 3 (EDN3) gene. Beta-1,4-Galactosyltransferase, polypeptide 1 (B4GALT1), and versikan (VCAN) genes have been proposed as candidate genes for Id. Later in 2017, the GRAM domain gene containing 3 (GRAND 3) was proposed as the most likely candidate gene for the Id locus. However, no mutations significantly associated with this trait were found in GRAND 3.As a result of a century-long history of studying the genes that determine skin color in chickens, exact associations with the sex-linked skin melanin inhibitor Id have not been determined. Thus, this problem requires further study.

Investigation of the Molecular Mechanisms by Which Endothelin-3 Stimulates Preadipocyte Growth

Endothelins induce many biological responses, and they are composed of three peptides: ET-1, ET-2, and ET-3. Reports have indicated that ET-1 regulates cell proliferation, adipogenesis, and other cell responses and that ET-3 stimulates the growth of gastrointestinal epithelial cells and melanocytes. However, the signalling pathways of ET3 that mediate the growth of fat cells are still unclear. Using 3T3-L1 white preadipocytes, we found that ET-3 induced increases in both cell number and BrdU incorporation. Pretreatment with an ETAR antagonist (but not an ETBR antagonist) blocked the ET-3-induced increases in both cell number and BrdU incorporation. Additionally, BQ610 suppressed the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3 proteins, and pretreatment with specific inhibitors of AMPK, JNK/c-JUN, or JAK/STAT3 prevented the ET-3-induced increases in phosphorylation of AMPK, c-JUN, and STAT3, respectively. Neither p38 MAPK inhibitor nor PKC inhibitor altered the effects of ET-3 on cell growth. These data suggest that ET-3 stimulates preadipocyte growth through the ETAR, AMPK, JNK/c-JUN, and STAT3 pathways. Moreover, ET-3 did not alter HIB1B brown preadipocyte and D12 beige preadipocyte growth, suggesting a preadipocyte type-dependent effect. The results of this study may help explain how endothelin mediates fat cell activity and fat cell-associated diseases.

Insights into Endothelin-3 and Multiple Sclerosis

Endothelins are powerful vasoconstrictor peptides that play numerous other roles. Endothelin-1 (ET1) is the principal isoform produced by the endothelium in the human cardiovascular system. Endothelin-3 (ET3) and its rPptor affinity have been demonstrated to support neuronal repair mechanisms throughout life. In multiple sclerosis (MS), the role of vasoactive peptides are not well defined. Here we focus on ET3, specifically the plasma levels between MS patients and healthy subjects. Furthermore, we evaluated the changes in ET1 and ET3 plasma levels during different disease phases, the correlation between ET3 and cerebral circulation time, and the relationship between ET1 and ET3. In MS patients, the ET3 plasma levels were altered in a time-dependent manner. These results could support a putative role of ET3 in neuroprotection and/or neuroimmune modulation over time.

Endothelin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Endothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [24]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1, endothelin-2 and endothelin-3).

Evolution of Endothelin signaling and diversification of adult pigment pattern in Danio fishes

Fishes of the genus Danio exhibit diverse pigment patterns that serve as useful models for understanding the genes and cell behaviors underlying the evolution of adult form. Among these species, zebrafish D. rerio exhibit several dark stripes of melanophores with sparse iridophores that alternate with light interstripes of dense iridophores and xanthophores. By contrast, the closely related species D. nigrofasciatus has an attenuated pattern with fewer melanophores, stripes and interstripes. Here we demonstrate species differences in iridophore development that presage the fully formed patterns. Using genetic and transgenic approaches we identify the secreted peptide Endothelin-3 (Edn3)—a known melanogenic factor of tetrapods—as contributing to reduced iridophore proliferation and fewer stripes and interstripes in D. nigrofasciatus. We further show the locus encoding this factor is expressed at lower levels in D. nigrofasciatus owing to cis-regulatory differences between species. Finally, we show that functions of two paralogous loci encoding Edn3 have been partitioned between skin and non-skin iridophores. Our findings reveal genetic and cellular mechanisms contributing to pattern differences between these species and suggest a model for evolutionary changes in Edn3 requirements across vertebrates.Author SummaryNeural crest derived pigment cells generate the spectacular variation in skin pigment patterns among vertebrates. Mammals and birds have just a single skin pigment cell, the melanocyte, whereas ectothermic vertebrates have several pigment cells including melanophores, iridophores and xanthophores, that together organize into a diverse array of patterns. In the teleost zebrafish, Danio rerio, an adult pattern of stripes depends on interactions between pigment cell classes and between pigment cells and their tissue environment. The close relative, D. nigrofasciatus has fewer stripes and prior analyses suggested a difference between these species that lies extrinsic to the pigment cells themselves. A candidate for mediating this difference is Endothelin-3 (Edn3), essential for melanocyte development in warm-blooded animals, and required by all three classes of pigment cells in an amphibian. We show that Edn3 specifically promotes iridophore development in Danio, and that differences in Edn3 expression contribute to differences in iridophore complements, and striping, between D. rerio and D. nigrofasciatus. Our study reveals a novel function for Edn3 and provides new insights into how changes in gene expression yield morphogenetic outcomes to effect diversification of adult form.