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Series GSE109102 Query DataSets for GSE109102
Status Public on Aug 20, 2019
Title Von Hippel-Lindau (VHL) mutations disrupt vascular patterning and maturation via Notch
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Von Hippel-Lindau (VHL) gene mutations induce neural tissue hemangioblastomas as well as highly vascularized clear cell renal cell carcinomas (ccRCCs). Pathological vessel remodeling arises from mis-regulation of hypoxia inducible factors and vascular endothelial growth factor, among other genes. Variation in disease penetrance has long been recognized in relation to genotype. We show Vhl mutations also disrupt Notch signaling, causing mutation-specific vascular abnormalities e.g. type 1 (null) vs. type 2B (murine G518A representing human R167Q). In conditional mutation retina vasculature, Vhl null mutation (i.e. UBCCreER/+; Vhlfl/fl) had little effect on initial vessel branching, but severely reduced arterial and venous branching at later stages. Interestingly, this mutation accelerated arterial maturation, as observed in retina vessel morphology and aberrant a-smooth muscle actin localization, particularly in vascular pericytes. RNA sequencing analysis identified gene expression changes within several key pathways including Notch and smooth muscle cell contractility. Notch inhibition failed to reverse later-stage branching defects but rescued the accelerated arterialization. Retinal vessels harboring the type 2B Vhl mutation (i.e. UBCCreER/+; Vhlfl/2B) displayed stage-specific changes in vessel branching and an advanced progression toward an arterial phenotype. Disrupting Notch signaling in 2B mutants increased both artery and vein branching, and restored arterial maturation toward non-mutant levels. By revealing differential effects of the null and type 2B Vhl mutations on vessel branching and maturation, these data may provide insight into the variability of VHL-associated vascular changes, particularly the heterogeneity and aggressiveness in ccRCC vessel growth, as well as suggest Notch pathway targets for treating VHL syndrome.
Overall design A total of eight mouse retinas (n=8) were submitted for RNAseq. There are four experimental groups with 2 replicates for each: 1) WT CreER VHL lox/lox; 2)WT CreER VHL2b/lox; 3) UBC CreER VHL lox/lox; and 4) UBC CreER VHL2b/lox
Contributor(s) Rathmell WK, Chappell JC
Citation(s) 29467323
Submission date Jan 11, 2018
Last update date Aug 20, 2019
Contact name Aguirre A de Cubas
Organization name Vanderbilt University Medical Center
Department Hematology and Oncology
Lab Rathmell Lab
Street address 2220 Pierce Ave
State/province TN
ZIP/Postal code 37232
Country USA
Platforms (1)
GPL21493 Illumina HiSeq 3000 (Mus musculus)
Samples (8)
GSM2931685 WT.CreER_VHL.lox-lox_rep1
GSM2931686 WT.CreER_VHL.lox-lox_rep2
GSM2931687 WT.CreER_VHL2B-lox_rep1
BioProject PRJNA429643
SRA SRP128915

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE109102_RAW.tar 2.1 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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