Interrogating the ccm-3 Gene Network

Abstract

Summary: 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. : Lant et al. use C. elegans genetics to better understand the human disease cerebral cavernous malformation (CCM). Through a whole-genome screen, and bioinformatics, they uncover a set of conserved genes that exhibit ccm-3 phenotypes. These targets may be able to inform therapeutic studies. Keywords: biological tubes, cerebral cavernous malformation, CCM3, C. elegans, endothelial cells, whole-genome screen, phenologs, bioinformatics