ZFIN ID: ZDB-PUB-190425-6
The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage
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.
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
PubMed: 31014480 Full text @ Dev. Cell
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.