PUBLICATION

PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation

Authors
Johansson, J.A., Marie, K.L., Lu, Y., Brombin, A., Santoriello, C., Zeng, Z., Zich, J., Gautier, P., von Kriegsheim, A., Brunsdon, H., Wheeler, A.P., Dreger, M., Houston, D.R., Dooley, C.M., Sims, A.H., Busch-Nentwich, E.M., Zon, L.I., Illingworth, R.S., Patton, E.E.
ID
ZDB-PUB-200712-8
Date
2020
Source
Developmental Cell   54(3): 317-332.e9 (Journal)
Registered Authors
Brombin, Alessandro, Busch-Nentwich, Elisabeth, Dooley, Christopher, Patton, E. Elizabeth, Santoriello, Cristina, Zeng, Zhiqiang, Zon, Leonard I.
Keywords
DDX21, MITF, PRL3, PTP4A3, melanocyte stem cell, melanoma, regeneration, small-molecule screen, transcription elongation, zebrafish
MeSH Terms
  • Animals
  • Cell Differentiation/genetics*
  • DEAD-box RNA Helicases/genetics
  • DEAD-box RNA Helicases/metabolism*
  • Gene Expression Regulation, Developmental
  • Humans
  • Melanocytes/cytology*
  • Melanoma/genetics
  • Melanoma/metabolism*
  • Microphthalmia-Associated Transcription Factor/genetics
  • Mutation
  • Neoplasm Proteins/genetics
  • Neoplasm Proteins/metabolism*
  • Protein Tyrosine Phosphatases/genetics
  • Protein Tyrosine Phosphatases/metabolism*
  • Stem Cells/metabolism
  • Zebrafish/metabolism
  • Zebrafish Proteins/metabolism
PubMed
32652076 Full text @ Dev. Cell
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes