PUBLICATION

The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function

Authors
Koltowska, K., Okuda, K.S., Gloger, M., Rondon-Galeano, M., Mason, E., Xuan, J., Dudczig, S., Chen, H., Arnold, H., Skoczylas, R., Bower, N.I., Paterson, S., Lagendijk, A.K., Baillie, G.J., Leshchiner, I., Simons, C., Smith, K.A., Goessling, W., Heath, J.K., Pearson, R.B., Sanij, E., Schulte-Merker, S., Hogan, B.M.
ID
ZDB-PUB-211110-4
Date
2021
Source
Nature cell biology   23: 1136-1147 (Journal)
Registered Authors
Dudczig, Stefanie, Goessling, Wolfram, Heath, Joan K., Hogan, Ben M., Mason, Elizabeth, Okuda, Kazuhide Shaun, Paterson, Scott, Schulte-Merker, Stefan, Smith, Kelly
Keywords
none
Datasets
GEO:GSE180330
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Cell Cycle Checkpoints
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21/genetics
  • Cyclin-Dependent Kinase Inhibitor p21/metabolism
  • DEAD-box RNA Helicases/genetics
  • DEAD-box RNA Helicases/metabolism*
  • Endothelial Cells/enzymology*
  • Gene Expression Regulation, Developmental
  • Human Umbilical Vein Endothelial Cells/enzymology
  • Humans
  • Lymphangiogenesis*
  • Lymphatic Vessels/embryology
  • Lymphatic Vessels/enzymology*
  • RNA, Ribosomal/biosynthesis*
  • RNA, Ribosomal/genetics
  • Ribosomes/genetics
  • Ribosomes/metabolism*
  • Signal Transduction
  • Tumor Suppressor Protein p53/genetics
  • Tumor Suppressor Protein p53/metabolism*
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor C/metabolism*
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Vascular Endothelial Growth Factor Receptor-3/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
34750583 Full text @ Nat. Cell Biol.
Abstract
The development of a functional vasculature requires the coordinated control of cell fate, lineage differentiation and network growth. Cellular proliferation is spatiotemporally regulated in developing vessels, but how this is orchestrated in different lineages is unknown. Here, using a zebrafish genetic screen for lymphatic-deficient mutants, we uncover a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates lymphatic vessel development. An established regulator of ribosomal RNA synthesis and ribosome biogenesis, Ddx21 is enriched in sprouting venous endothelial cells in response to Vegfc-Flt4 signalling. Ddx21 function is essential for Vegfc-Flt4-driven endothelial cell proliferation. In the absence of Ddx21, endothelial cells show reduced ribosome biogenesis, p53 and p21 upregulation and cell cycle arrest that blocks lymphangiogenesis. Thus, Ddx21 coordinates the lymphatic endothelial cell response to Vegfc-Flt4 signalling by balancing ribosome biogenesis and p53 function. This mechanism may be targetable in diseases of excessive lymphangiogenesis such as cancer metastasis or lymphatic malformation.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping