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Interrogating the ccm-3 Gene Network.
- Source :
-
Cell reports [Cell Rep] 2018 Sep 11; Vol. 24 (11), pp. 2857-2868.e4. - Publication Year :
- 2018
-
Abstract
- Cerebral cavernous malformations (CCMs) are neurovascular lesions caused by mutations in one of three genes (CCM1-3). Loss of CCM3 causes the poorest prognosis, and little is known about how it regulates vascular integrity. The C. elegans ccm-3 gene regulates the development of biological tubes that resemble mammalian vasculature, and in a genome-wide reverse genetic screen, we identified more than 500 possible CCM-3 pathway genes. With a phenolog-like approach, we generated a human CCM signaling network and identified 29 genes in common, of which 14 are required for excretory canal extension and membrane integrity, similar to ccm-3. Notably, depletion of the MO25 ortholog mop-25.2 causes severe defects in tube integrity by preventing CCM-3 localization to apical membranes. Furthermore, loss of MO25 phenocopies CCM3 ablation by causing stress fiber formation in endothelial cells. This work deepens our understanding of how CCM3 regulates vascular integrity and may help identify therapeutic targets for treating CCM3 patients.<br /> (Copyright © 2018 Hospital for Sick Children. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis genetics
Apoptosis physiology
Apoptosis Regulatory Proteins genetics
Caenorhabditis elegans
Caenorhabditis elegans Proteins genetics
Carrier Proteins genetics
Carrier Proteins metabolism
Endothelial Cells metabolism
Gene Regulatory Networks genetics
Gene Regulatory Networks physiology
Membrane Proteins genetics
Mutation genetics
Signal Transduction genetics
Signal Transduction physiology
Apoptosis Regulatory Proteins metabolism
Caenorhabditis elegans Proteins metabolism
Membrane Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 24
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 30208312
- Full Text :
- https://doi.org/10.1016/j.celrep.2018.08.039