Centre for Integrative Genetics, Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, NO-1430 Ås, Norway.
University of Rochester Medical Center, School of Medicine and Dentistry, Department of Pharmacology and Physiology, Rochester, NY 14642, USA.
Sci Rep. 2016 Jul 4;6:28969. doi: 10.1038/srep28969.
In many vertebrate species visible melanin-based pigmentation patterns correlate with high stress- and disease-resistance, but proximate mechanisms for this trait association remain enigmatic. Here we show that a missense mutation in a classical pigmentation gene, melanocyte stimulating hormone receptor (MC1R), is strongly associated with distinct differences in steroidogenic melanocortin 2 receptor (MC2R) mRNA expression between high- (HR) and low-responsive (LR) rainbow trout (Oncorhynchus mykiss). We also show experimentally that cortisol implants increase the expression of agouti signaling protein (ASIP) mRNA in skin, likely explaining the association between HR-traits and reduced skin melanin patterning. Molecular dynamics simulations predict that melanocortin 2 receptor accessory protein (MRAP), needed for MC2R function, binds differently to the two MC1R variants. Considering that mRNA for MC2R and the MC1R variants are present in head kidney cells, we hypothesized that MC2R activity is modulated in part by different binding affinities of the MC1R variants for MRAP. Experiments in mammalian cells confirmed that trout MRAP interacts with the two trout MC1R variants and MC2R, but failed to detect regulation of MC2R signaling, possibly due to high constitutive MC1R activity.
在许多脊椎动物物种中，可见的黑色素基色素沉着模式与高应激和疾病抵抗力相关，但这种特征关联的直接机制仍然是个谜。在这里，我们表明，经典色素沉着基因黑色素细胞刺激激素受体（MC1R）中的一个错义突变与高反应（HR）和低反应（LR）虹鳟鱼（Oncorhynchus mykiss）之间类固醇生成黑素皮质素 2 受体（MC2R）mRNA 表达的明显差异密切相关。我们还通过实验表明，皮质醇植入物增加了皮肤中促黑皮质素信号蛋白（ASIP）mRNA 的表达，这可能解释了 HR 特征与减少皮肤黑色素模式之间的关联。分子动力学模拟预测，黑素皮质素 2 受体辅助蛋白（MRAP），这是 MC2R 功能所必需的，与两种 MC1R 变体的结合方式不同。考虑到 MC2R 和 MC1R 变体的 mRNA 存在于头部肾脏细胞中，我们假设 MC2R 活性部分受到 MC1R 变体与 MRAP 不同结合亲和力的调节。哺乳动物细胞实验证实，鳟鱼 MRAP 与两种鳟鱼 MC1R 变体和 MC2R 相互作用，但未能检测到 MC2R 信号的调节，这可能是由于 MC1R 活性较高。
