Johansson JA, Marie KL, Lu Y, Brombin A, Santoriello C, Zeng Z, Zich J, Gautier P, von Kriegsheim A, Brunsdon H, Wheeler AP, Dreger M, Houston DR, Dooley CM, Sims AH, Busch-Nentwich EM, Zon LI, Illingworth RS, Patton EE. PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Dev Cell. 2020 Jul 08.

Citation

Johansson JA, Marie KL, Lu Y, Brombin A, Santoriello C, Zeng Z, Zich J, Gautier P, von Kriegsheim A, Brunsdon H, Wheeler AP, Dreger M, Houston DR, Dooley CM, Sims AH, Busch-Nentwich EM, Zon LI, Illingworth RS, Patton EE. 2020. PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Developmental cell. 54(3):317-332.e9. Pubmed: 32652076 DOI:S1534-5807(20)30463-9

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 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.

Related Faculty

Leonard Zon, M.D.

Zon Lab

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.