PUBLICATION

The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage

Authors
Baek, S., Oh, T.G., Secker, G., Sutton, D.L., Okuda, K.S., Paterson, S., Bower, N.I., Toubia, J., Koltowska, K., Capon, S.J., Baillie, G.J., Simons, C., Muscat, G.E.O., Lagendijk, A.K., Smith, K.A., Harvey, N.L., Hogan, B.M.
ID
ZDB-PUB-190425-6
Date
2019
Source
Developmental Cell   49: 279-292.e5 (Journal)
Registered Authors
Capon, Sam, Hogan, Ben M., Okuda, Kazuhide Shaun, Paterson, Scott, Smith, Kelly
Keywords
Nova2, Prox1, RNA splicing, lymphangiogenesis, lymphatics, signaling, vascular
MeSH Terms
  • Alternative Splicing
  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Endothelial Cells/cytology
  • Endothelial Cells/metabolism
  • Female
  • Homeodomain Proteins/metabolism
  • Humans
  • Lymphangiogenesis
  • Lymphatic Vessels/cytology
  • Lymphatic Vessels/metabolism*
  • MAP Kinase Signaling System*
  • Male
  • Nerve Tissue Proteins/metabolism*
  • RNA-Binding Proteins/metabolism*
  • Tumor Suppressor Proteins/metabolism
  • Veins/cytology
  • Veins/metabolism
  • Zebrafish
(all 20)
PubMed
31014480 Full text @ Dev. Cell
Abstract
The correct assignment of cell fate within fields of multipotent progenitors is essential for accurate tissue diversification. The first lymphatic vessels arise from pre-existing veins after venous endothelial cells become specified as lymphatic progenitors. Prox1 specifies lymphatic fate and labels these progenitors; however, the mechanisms restricting Prox1 expression and limiting the progenitor pool remain unknown. We identified a zebrafish mutant that displayed premature, expanded, and prolonged lymphatic specification. The gene responsible encodes the regulator of alternative splicing, Nova2. In zebrafish and human endothelial cells, Nova2 selectively regulates pre-mRNA splicing for components of signaling pathways and phosphoproteins. Nova2-deficient endothelial cells display increased Mapk/Erk signaling, and Prox1 expression is dynamically controlled by Erk signaling. We identify a mechanism whereby Nova2-regulated splicing constrains Erk signaling, thus limiting lymphatic progenitor cell specification. This identifies the capacity of a factor that tunes mRNA splicing to control assignment of cell fate during vascular differentiation.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
nova2uq14bh/uq14bhstandard conditionsLong-pec
nova2uq14bh/uq14bh; nz101Tg; y7Tgstandard conditionsLong-pec
nova2uq14bh/uq14bh; nz101Tg; y7Tgstandard conditionsLong-pec
nova2uq14bh/uq14bh; nz101Tg; y7Tgstandard conditionsLong-pec
nova2uq14bh/uq14bh; nz101Tg; y7Tgstandard conditionsLong-pec
nova2uq14bh/uq14bh; nz101Tg; y7Tgstandard conditionsDay 5
nova2uq14bh/uq14bh; y7Tgstandard conditionsPrim-5
nova2uq14bh/uq14bh; y7Tgstandard conditionsPrim-5
nova2uq14bh/uq14bh; y7Tgstandard conditionsPrim-15
nova2uq14bh/uq14bh; y7Tgstandard conditionsPrim-15
1 - 10 of 13
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
io011
    		Indel
    nz101TgTransgenic Insertion
      s843TgTransgenic Insertion
        uq14bh
          		Insertion
          uq37bhTgTransgenic Insertion
            uq40bhTgTransgenic Insertion
              uq41bhTgTransgenic Insertion
                y1TgTransgenic Insertion
                  y7TgTransgenic Insertion
                    1 - 9 of 9
                    Show
                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    Target Reagent Reagent Type
                    ccbe1MO1-ccbe1MRPHLNO
                    flt4MO3-flt4MRPHLNO
                    nova2CRISPR1-nova2CRISPR
                    vegfcMO1-vegfcMRPHLNO
                    1 - 4 of 4
                    Show
                    Fish
                    Fish
                    nova2uq14bh/+; nz101Tg; y7Tg
                    nova2uq14bh; y7Tg
                    nova2uq14bh/+; y7Tg
                    nova2uq14bh/uq14bh
                    nova2uq14bh/uq14bh; nz101Tg; y7Tg
                    nova2uq14bh/uq14bh; y7Tg
                    uq37bhTg; uq40bhTg
                    uq40bhTg
                    WT
                    y7Tg
                    1 - 10 of 10
                    Show
                    Antibodies
                    Orthology
                    Engineered Foreign Genes
                    Marker Marker Type Name
                    DsRedEFGDsRed
                    EGFPEFGEGFP
                    GFPEFGGFP
                    mCherryEFGmCherry
                    YFPEFGYFP
                    1 - 5 of 5
                    Show
                    Mapping
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                    Citation
                    Baek, S., Oh, T.G., Secker, G., Sutton, D.L., Okuda, K.S., Paterson, S., Bower, N.I., Toubia, J., Koltowska, K., Capon, S.J., Baillie, G.J., Simons, C., Muscat, G.E.O., Lagendijk, A.K., Smith, K.A., Harvey, N.L., Hogan, B.M. (2019) The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage. Developmental Cell. 49:279-292.e5.