The TSC1/2 Complex Controls Drosophila Pigmentation through TORC1-Dependent Regulation of Catecholamine Biosynthesis

In Drosophila, the pattern of adult pigmentation is initiated during late pupal stages by the production of catecholamines DOPA and dopamine, which are converted to melanin. The pattern and degree of melanin deposition is controlled by the expression of genes such as ebony and yellow as well as by the enzymes involved in catecholamine biosynthesis. In this study, we show that the conserved TSC/TORC1 cell growth pathway controls catecholamine biosynthesis in Drosophila during pigmentation. We find that high levels of Rheb, an activator of the TORC1 complex, promote premature pigmentation in the mechanosensory bristles during pupal stages, and alter pigmentation in the cuticle of the adult fly. Disrupting either melanin synthesis by RNAi knockdown of melanogenic enzymes such as tyrosine hydroxylase (TH), or downregulating TORC1 activity by Raptor knockdown, suppresses the Rheb-dependent pigmentation phenotype in vivo. Increased Rheb activity drives pigmentation by increasing levels of TH in epidermal cells. Our findings indicate that control of pigmentation is linked to the cellular nutrient-sensing pathway by regulating levels of a critical enzyme in melanogenesis, providing further evidence that inappropriate activation of TORC1, a hallmark of the human tuberous sclerosis complex tumor syndrome disorder, can alter metabolic and differentiation pathways in unexpected ways.在果蝇（Drosophila）中，成虫色素沉着模式于蛹晚期由儿茶酚胺类物质DOPA（多巴）与多巴胺的合成启动，二者可进一步转化为黑色素（melanin）。黑色素沉积的模式与程度，受黑檀基因（ebony）、黄基因（yellow）等基因的表达，以及参与儿茶酚胺生物合成的酶类共同调控。本研究发现，保守的TSC/TORC1细胞生长通路可在果蝇色素沉着过程中调控儿茶酚胺的生物合成。我们观察到，高表达TORC1复合物的激活因子Rheb，会在蛹期诱导机械感觉刚毛提前出现色素沉着，并改变成虫表皮的色素沉积状态。通过RNA干扰敲降酪氨酸羟化酶（tyrosine hydroxylase, TH）等黑色素生成酶以阻断黑色素合成，或是通过敲降Raptor以下调TORC1活性，均可在体内抑制Rheb依赖的色素沉着表型。增强的Rheb活性通过提升表皮细胞内TH的蛋白水平来促进色素沉着。本研究结果表明，色素沉着的调控可通过调控黑色素生成通路中关键酶的表达水平，与细胞营养感应通路建立功能关联；这进一步证实，作为人类结节性硬化复合物肿瘤综合征标志性特征的TORC1异常激活，可通过意想不到的方式改变代谢与分化通路。