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The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling

ABSTRACT: The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling

PROVIDER: PRJNA748172 | ENA |

REPOSITORIES: ENA

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The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [human]

Project description:The development of a differentiated and functional vasculature requires coordinated control of cell fate specification, lineage differentiation and vascular network growth. Cellular proliferation is spatiotemporally regulated in developing vessel networks but how this is achieved and differentially controlled in specific lineages is unknown. Using a zebrafish forward genetic screen for mutants that form blood vessels but fail to form lymphatic vessels, we uncovered a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates the early development of lymphatic endothelial cells. Ddx21 is essential for Vegfc-Vegfr3 driven endothelial cell proliferation. Ddx21 is an established regulator of ribosomal RNA transcription and in the absence of Ddx21, mutant lymphatic endothelial cells show reduced ribosome biogenesis. Ultimately, loss of Ddx21 leads to a p53-p21 dependent cell cycle arrest that blocks embryonic lymphangiogenesis. Thus, the RNA helicase Ddx21 coordinates the endothelial cell proliferative response to Vegfc-Vegfr3 signalling by balancing ribosome biogenesis and p53-p21 signalling. This mechanism may have therapeutic potential in diseases of excessive lymphangiogenesis such as in cancer metastasis or lymphatic malformation.

2021-09-09 | GSE179868 | GEO

The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [zebrafish]

2021-09-09 | GSE158566 | GEO

The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [zebrafish]

Project description:The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [zebrafish]

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The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [human]

Project description:The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling [human]

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The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53-p21 signalling

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-09-09 | GSE180330 | GEO

Specific fibroblast subpopulations and neuronal structures serve as local sources of Vegfc-processing components during lymphangiogenesis

Project description:Proteolytical processing of the growth factor VEGFC through the concerted activity of CCBE1 and ADAMTS3 is required for lymphatic development to occur. How these factors act together in time and space, and which cell types produce these factors is not understood. Here we assess the function of Adamts3 and the related protease Adamts14 during zebrafish lymphangiogenesis and show both proteins to be able to process Vegfc. Only the simultaneous loss of both protein functions results in lymphatic defects identical to vegfc loss-of-function situations. Cell transplantation experiments demonstrate neuronal structures and/or fibroblasts to constitute cellular sources not only for both proteases but also for Ccbe1 and Vegfc. We further show that it is the local restriction of Vegfc maturation which is needed to trigger normal lymphatic sprouting and directional migration. Our data provide a single-cell resolution model for establishing secretion and processing hubs for Vegfc during developmental lymphangiogenesis

2020-04-28 | GSE146923 | GEO

RNA helicase DDX21 coordinates transcription and noncoding RNA processing of the ribosomal pathway

Project description:DEAD-box RNA helicases are vital for the regulation of various aspects of the RNA life cycle, but the molecular underpinnings of their involvement, particularly in mammalian cells, remain poorly understood. Here we show that the DEAD-box RNA helicase DDX21 can sense transcriptional status of both RNA Pol I and Pol II to control transcriptional and post-transcriptional steps of ribosome biogenesis in human cells. We demonstrate that DDX21 widely associates with Pol I- and Pol II-transcribed genes and with diverse species of protein-coding and noncoding RNAs. Although broad, these molecular interactions, both at the chromatin and at the RNA level, exhibit a remarkable specificity for the ribosomal pathway. In the nucleolus, DDX21 occupies the transcribed rDNA locus, directly contacts both rRNA and snoRNAs and, as a functional component of the snoRNA ribonucleoprotein (snoRNP) complex, promotes modification of rRNA. In the nucleoplasm, DDX21 is incorporated into the 7SK snRNP complex, which facilitates DDX21 association with promoters of Pol II-transcribed genes encoding ribosomal proteins and snoRNAs. Promoter-bound DDX21 facilitates the release of P-TEFb from the 7SK snRNP, enhancing productive Pol II elongation. Altogether, we present a unifying mechanism for the coordinated regulation of ribosomal genes across nuclear compartments, and provide first evidence implicating a mammalian RNA helicase in RNA modification and Pol II elongation control. Examination of DDX21 chromatin association and DDX21 RNA interacting partners in HEK293 cells

2014-11-17 | E-GEOD-56802 | biostudies-arrayexpress

Macrophage-produced VEGFC is induced by efferocytosis to resolve inflammation and improve ventricular function after myocardial infarction (RNA-Seq)

Project description:Recent reports have suggested a protective role for vascular endothelial growth factor C (VEGFC) during acute cardiac lymphangiogenesis post MI. Glinton et al. report that defective efferocytosis by macrophages after experimental MI leads to a reduction in cardiac lymphangiogenesis and Vegfc expression.

2022-03-31 | GSE196866 | GEO

Macrophage-produced VEGFC is induced by efferocytosis to resolve inflammation and improve ventricular function after myocardial infarction (ChIP-Seq)

2022-03-31 | GSE196865 | GEO

VEGFC Upregulates Trans-Lymphatic Colorectal Cancer Metastasis in the Liver via Recruiting Bone Marrow Derived Cells

Project description:While colorectal cancer liver metastasis (CRCLM) is major cause of death of colorectal cancer, the mechanism of intrahepatic dissemination (trans-lymphatic metastasis) is not fully elucidated. Lymphangiogenesis can be the mechanism of the dissemination, but there are few evidences to prove it. In this study, we attempted to clarify the mechanism using syngeneic murine CRCLM model, especially focusing on vascular endothelial growth factor C (VEGFC), a promoter of lymphangiogenesis. We confirmed that 1) intrahepatic metastasis of CRCLM via lymphatic vessels was seen and lymphangiogenesis was upregulated in the CRCLM-bearing liver, 2) the degree of lymphangiogenesis and CRCLM was significantly correlated with the expression of VEGFC in colorectal cancer (CRC) cells and 3) macrophage inflammatory protein-1α (MIP-1α) was released from CRC cells under the stimulation of VEGFC and induced migration of immature bone marrow derived cells into the liver and differentiation into macrophage, which promoted dissemination of CRCLM. These findings suggest the possibility of therapeutic strategy targeting VEGFC / MIP-1α for diminishing CRCLM. In conclusion, VEGFC in CRC cells promoted trans-lymphatic metastasis of CRCLM by upregulation of lymphangiogenesis directly and indirectly via induction of macrophages derived from bone marrow cells.

2018-09-30 | GSE113235 | GEO

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