Weill Cornell Graduate School of Medical Sciences, Cell and Developmental Biology Program, New York, NY 10065, USA; Memorial Sloan Kettering Cancer Center, Department of Cancer Biology & Genetics, New York, NY 10065, USA.
Memorial Sloan Kettering Cancer Center, Department of Cancer Biology & Genetics, New York, NY 10065, USA.
Dev Cell. 2018 Jun 4;45(5):580-594.e7. doi: 10.1016/j.devcel.2018.04.025. Epub 2018 May 24.
Patterning of vertebrate melanophores is essential for mate selection and protection from UV-induced damage. Patterning can be influenced by circulating long-range factors, such as hormones, but it is unclear how their activity is controlled in recipient cells to prevent excesses in cell number and migration. The zebrafish wanderlust mutant harbors a mutation in the sheddase bace2 and exhibits hyperdendritic and hyperproliferative melanophores that localize to aberrant sites. We performed a chemical screen to identify suppressors of the wanderlust phenotype and found that inhibition of insulin/PI3Kγ/mTOR signaling rescues the defect. In normal physiology, Bace2 cleaves the insulin receptor, whereas its loss results in hyperactive insulin/PI3K/mTOR signaling. Insulin B, an isoform enriched in the head, drives the melanophore defect. These results suggest that insulin signaling is negatively regulated by melanophore-specific expression of a sheddase, highlighting how long-distance factors can be regulated in a cell-type-specific manner.
脊椎动物黑色素细胞的形成对于配偶选择和防止紫外线损伤至关重要。这种形成可以受到循环长距离因子的影响，例如激素，但目前尚不清楚它们在受体细胞中的活性如何受到控制，以防止细胞数量和迁移过度。斑马鱼 Wanderlust 突变体携带一种剪接酶 Bace2 的突变，表现出过度分枝和过度增殖的黑色素细胞，这些黑色素细胞定位于异常部位。我们进行了化学筛选，以鉴定 Wanderlust 表型的抑制因子，发现抑制胰岛素/PI3Kγ/mTOR 信号通路可以挽救缺陷。在正常生理条件下，Bace2 切割胰岛素受体，而其缺失会导致过度活跃的胰岛素/PI3Kγ/mTOR 信号通路。富含头部的胰岛素 B 异构体驱动黑色素细胞缺陷。这些结果表明，胰岛素信号受到黑色素细胞特异性表达的一种剪接酶的负调控，突出了长距离因子如何以细胞类型特异性的方式进行调节。
