Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.

黑素细胞在整个生命过程中由黑素细胞干细胞 (MSC) 补充，在色素沉着和黑色素瘤中发挥着关键作用。在这里，我们揭示了再生肝转移相关磷酸酶 3 (PRL3) 在 MSC 再生中的功能。我们发现 PRL3 与 RNA 解旋酶 DDX21 结合，从而限制 RNAPII 在主转录因子 (MITF) 调节的内溶酶体囊泡基因上的生产性转录。在斑马鱼中，这种机制控制着黑色素细胞的过早扩张和间充质干细胞的分化。在黑色素瘤患者中，这种内溶酶体囊泡途径的受限转录是PRL3 高黑色素瘤的标志。我们的工作提出了概念上的进展，即 PRL3 介导的转录延伸控制是活化 MSC 的分化检查点机制，并且与再生组织和癌症中 PRL3 的活性具有临床相关性。