Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 ( gpr126 ) mutant
Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 ( gpr126 ) mutant
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修复斑马鱼adgrg6 ( gpr126 ) 突变体中耳和髓鞘形成缺陷的化合物的鉴定
DOI：
10.1101/520056
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Diamantopoulou E
中科院分区：
文献类型：
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作者：
Diamantopoulou E
Adgrg6（Gpr126）是一种粘附G类蛋白偶联受体，在外周神经系统的髓鞘形成中具有保守作用。在斑马鱼中，adgrg6的突变也会导致内耳缺陷：耳组织不能下调versicangene的表达，形态发生被破坏。我们设计了一个全动物筛选，测试突变胚胎中上调和下调基因表达的拯救，以及弱等位基因和强等位基因的分析。从3120种结构不同的化合物中筛选，我们已经鉴定出68种在adgrg 6突变耳中降低多能蛋白聚糖b表达的化合物，其中41种还恢复突变胚胎的雪旺细胞中髓鞘碱性蛋白基因的表达。19种化合物不能拯救一个强adgrg6等位基因提供了候选分子，可能直接与Adgrg6受体相互作用。我们的管道提供了一种强有力的方法来识别调节GPCR活性的化合物，对未来的药物设计具有潜在的影响。
Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation ofadgrg6also results in defects in the inner ear: otic tissue fails to down-regulateversicangene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduceversican bexpression in theadgrg6mutant ear, 41 of which also restoremyelin basic proteingene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strongadgrg6allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design.