Abstract
Zebrafish has emerged as a powerful model organism for high throughput drug screening. Several morphological criteria, transgenic lines and in situ expression screens have been developed to identify novel bioactive compounds and their mechanism of action. Here, we used the inhibition of melanogenesis during early zebrafish embryo development to identify natural compounds that block melanogenesis. We identified an extract from the Greek hawthorn Crataegus pycnoloba as a potent inhibitor of melanin synthesis and used activity based subfractionation to identify active subfractions and eventually three single compounds of the same family (dibenzofurans). These compounds show reversible inhibition of melanin synthesis and do not act via inhibition of tyrosinase. We also showed that they do not interfere with neural crest differentiation or migration. We identified via in silico modeling that the compounds can bind to the aryl hydrocarbon receptor (AHR) and verified activation of the Ahr signaling pathway showing the induction of the expression of target genes.
Highlights
Melanin is synthesized in melanosomes, special organelles within the melanocytes, via a process called melanogenesis
We used in vivo phenotypic zebrafish assays and we searched for extracts that inhibit melanogenesis of zebrafish embryos
Zebrafish embryos at 24 hpf were treated with extracts at concentrations ranging from 0.001 to 0.1 mg/mL and the effect on the development of melanocytes was recorded at 48 hpf
Summary
Melanin is synthesized in melanosomes, special organelles within the melanocytes, via a process called melanogenesis. The amount, the type and the distribution pattern of melanin determine the actual skin, hair and eye color of humans and animals (Park et al, 2009). Melanogenesis is a complex metabolic pathway that combines enzymatically catalyzed and spontaneous chemical reactions. It is initiated by the hydroxylation of tyrosine to L-DOPA (3,4-dihydroxyphenylalanine), which further undergoes oxidation to dopaquinone. Both of these reactions are catalyzed by the key enzyme tyrosinase (TYR) and comprise the rate limiting steps in melanin synthesis, since the rest of the synthesis can proceed spontaneously at physiological pH. Two main pathways diversify, leading in the end to the synthesis of two types of melanin, the black– brown eumelanin and the yellow–red pheomelanin (Chang, 2012; Speeckaert et al, 2014)
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