The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function
淋巴管新生
细胞生物学
生物
遗传学
癌症
转移
作者
Katarzyna Koltowska,Kazuhide S. Okuda,Marleen Gloger,Maria Rondon‐Galeano,Elizabeth A. Mason,Jiachen Xuan,Stefanie Dudczig,Huijun Chen,Hannah Arnold,Renae Skoczylas,Neil I. Bower,Scott Paterson,Anne Karine Lagendijk,Gregory J. Baillie,Ignaty Leshchiner,Cas Simons,Kelly Smith,Wolfram Goessling,Joan K. Heath,Richard B. Pearson,Elaine Sanij,Stefan Schulte‐Merker,Benjamin M. Hogan
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.