|
| Status |
Public on Sep 29, 2017 |
| Title |
Notch1 haploinsufficiency causes aortic aneurysms in mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Ascending aortic aneurysms (AscAA) are a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype. Lineage tracing analysis showed that loss of Notch1 in the SHF reduces the number of SHF-derived smooth muscle cells in the aortic root, and RNA-seq analysis demonstrated distinct in vivo expression patterns between lineage-specific regions of the ascending aorta. Finally, Notch1+/- mice in a predominantly 129S6 background develop aortic root dilation, indicating that loss of Notch1 independently predisposes to AscAA. These findings are the first to demonstrate a SHF lineage-specific role for Notch1 in AscAA and suggest that genes linked to the development of BAV may also contribute to the associated aortopathy.
|
| |
|
| Overall design |
To determine why dilation was localized to the aortic root in Notch1.129S6+/- mice, RNA-sequencing was performed on proximal and distal ascending aortic tissue from Notch1.129S6+/- mice and wildtype littermates at 2 months of age. Transcriptome analysis was utilized to better understand why the dilation was localized to the aortic root. Hierarchical cluster analysis grouped these samples based on location first and then genotype, and showed that cells of the proximal and distal ascending aorta have distinct gene expression patterns in vivo.
|
| |
|
| Contributor(s) |
Koenig SN, LaHaye S, Feller JD, LaHaye S, Rowland P, Hor KN, Trask AJ, Janssen PM, Radtke F, Lilly B, Garg V |
| Citation(s) |
29093270 |
| |
| Submission date |
Sep 28, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Vidu Garg |
| E-mail(s) |
vidu.garg@nationwidechildrens.org
|
| Phone |
614-355-5710
|
| Organization name |
Research Institute at Nationwide Children's Hospital
|
| Department |
Cardiovascular Research
|
| Lab |
Vidu Garg
|
| Street address |
700 Children's Drive WB4239
|
| City |
Columbus |
| State/province |
OH |
| ZIP/Postal code |
43205 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (12)
|
|
| Relations |
| BioProject |
PRJNA412455 |
| SRA |
SRP119033 |
Less...
More...