The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function.
Nat Cell Biol
; 23(11): 1136-1147, 2021 11.
Article
en En
| MEDLINE
| ID: mdl-34750583
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ribosomas
/
ARN Ribosómico
/
Proteína p53 Supresora de Tumor
/
Proteínas de Pez Cebra
/
Células Endoteliales
/
Vasos Linfáticos
/
Factor C de Crecimiento Endotelial Vascular
/
Linfangiogénesis
/
Proliferación Celular
/
ARN Helicasas DEAD-box
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Cell Biol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Australia