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

Hogan and colleagues report that the RNA helicase Ddx21 mediates Vegfc-stimulated lymphangiogenesis during zebrafish development through controlling rDNA transcription and ribosome biogenesis in endothelial cells. 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.

Automated summary

The RNA helicase Ddx21 plays a crucial role in mediating Vegfc-stimulated lymphangiogenesis by controlling rDNA transcription and ribosome biogenesis in endothelial cells. It regulates cell proliferation and balances p53 function in response to Vegfc-Flt4 signaling, essential for the development of lymphatic vessels. This mechanism could be a potential target for diseases involving excessive lymphangiogenesis, such as cancer metastasis or lymphatic malformation.