1. The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function
- Author
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Huijun Chen, Gregory J. Baillie, Richard B. Pearson, Elaine Sanij, Neil I. Bower, Marleen Gloger, Benjamin M. Hogan, Joan K. Heath, Kelly A. Smith, Maria Rondon-Galeano, Scott Paterson, Cas Simons, Stefan Schulte-Merker, Jiachen Xuan, Renae Skoczylas, Anne K. Lagendijk, Wolfram Goessling, Hannah Arnold, Ignaty Leshchiner, Stefanie Dudczig, Kazuhide S. Okuda, Katarzyna Koltowska, and Elizabeth Mason
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Vascular Endothelial Growth Factor C ,Ribosome biogenesis ,Cell fate determination ,Animals, Genetically Modified ,DEAD-box RNA Helicases ,Downregulation and upregulation ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Lymphangiogenesis ,Zebrafish ,Cells, Cultured ,Cell Proliferation ,Lymphatic Vessels ,biology ,Endothelial Cells ,Gene Expression Regulation, Developmental ,Cell Cycle Checkpoints ,Cell Biology ,Zebrafish Proteins ,Vascular Endothelial Growth Factor Receptor-3 ,biology.organism_classification ,RNA Helicase A ,Cell biology ,Endothelial stem cell ,Vascular endothelial growth factor C ,RNA, Ribosomal ,Tumor Suppressor Protein p53 ,Ribosomes ,Signal Transduction - 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.
- Published
- 2021