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
  • Neoplasm Proteins/genetics
  • Neoplasm Proteins/metabolism*
  • Stem Cells/metabolism
  • Animals
  • Zebrafish/metabolism
  • Gene Expression Regulation, Developmental
  • Melanocytes/cytology*
  • DEAD-box RNA Helicases/genetics
  • DEAD-box RNA Helicases/metabolism*
  • Melanoma/genetics
  • Melanoma/metabolism*
  • Microphthalmia-Associated Transcription Factor/genetics
  • Cell Differentiation/genetics*
  • Protein Tyrosine Phosphatases/genetics
  • Protein Tyrosine Phosphatases/metabolism*
  • Humans
  • Mutation
  • Zebrafish Proteins/metabolism
(all 18)
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
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ue403TgTransgenic Insertion
    ue404
      Small Deletion
      ue405
        Small Deletion
        vc7
          Point Mutation
          w47TgTransgenic Insertion
            zf148TgTransgenic Insertion
              1 - 6 of 6
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              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              1 - 5 of 5
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              Fish
              Antibodies
              Name Type Antigen Genes Isotypes Host Organism
              Ab1-ddx21monoclonal
                IgGRabbit
                Ab1-ptp4a3monoclonal
                  IgG1Mouse
                  Ab2-ddx21monoclonal
                    IgG1Mouse
                    Ab2-mitfpolyclonal
                      IgGRabbit
                      Ab3-ddx21polyclonal
                        IgGRabbit
                        1 - 5 of 5
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                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        DsRedEFGDsRed
                        EGFPEFGEGFP
                        GFPEFGGFP
                        1 - 3 of 3
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                        Mapping
                        No data available