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PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

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Original languageEnglish
JournalDevelopmental Cell
Early online date10 Jul 2020
DOIs
Publication statusE-pub ahead of print - 10 Jul 2020

Abstract

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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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.

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