The CCM-3 Gene Network

Abstract

Mechanisms that control biological tube development and integrity are conserved from C. elegans to human, and defects in these processes cause a variety of diseases. Cerebral cavernous malformations (CCM) are neurovascular lesions caused by inactivating mutations in one of three genes (CCM1-3), with loss of CCM3 causing the earliest onset and poorest prognosis. Of the three CCM genes, the least is known about how CCM3 regulates vascular integrity. The C. elegans CCM3 gene (ccm-3) is required for proper development of biological tubes that resemble mammalian vasculature, including the excretory canal and germline. By exploiting a synthetic lethal interaction between ccm-3 and the CCM1 homolog kri-1 we conducted a genome-wide screen and identified over 500 genes that exhibit negative interactions with kri-1. In parallel, we employed a phenolog-like approach using the bioinformatics platforms GeneMANIA and STRING to generate a predicted CCM gene network from a short list of proteins that function in CCM signalling. Comparison of these two data sets revealed 31 genes in common that are conserved from worm to human, of which 14 are required for excretory canal extension and membrane integrity, similar to ccm-3. Depletion of the MO25 ortholog mop-25.2 caused the most severe defects in excretory canal extension and germline membrane integrity by preventing CCM-3 localization to apical membranes. This work deepens our understanding of how CCM3 regulates vascular integrity, and may help identify therapeutic targets that can be exploited for treating CCM3 patients.