Cerebral Cavernous malformations (CCMs) are the disorders of capillaries in the central nervous system that result from a loss of integrity in endothelial cells. CCMs affect approximately 1 in 500 individuals and presents in patients a variety of pathophysiological symptoms that range from mild headaches to severe hemorrhagic stroke. Till date, mutations in three genes have been identified that account for approximately 90% of patients with familial disease, ccm-1, ccm-2 and ccm-3. The most severe prognosis is associated with ccm-3 mutations, but the CCM3 signalling pathway has not been resolved. In contrast to the familial form, sporadic CCMs have not been linked with any genetic loci. The varying degrees of symptoms and severity of disease in patients with the same mutation in either of the familial CCM genes suggests the existence of modifier genes. We have shown that ccm-3 (or C14A4.11) affects multiple tissues in C. elegans. For example, ccm-3 homozygote mutants have truncated excretory canals as well as defective oocyte and spermatocyte development that renders them sterile. The oocytes do not grow to the proper size and undergo massive waves of apoptosis, which can be rescued by expression of wild-type ccm-3 gene. Because mammalian CCM genes have been shown to affect reactive oxygen species (ROS), we cultivated ccm-3 mutants in presence of N-acetyl cysteine (NAC), a ROS scavenger, and observed partial rescue of the germline phenotype. NAC also partially protected germlines of wild-type animals from radiation-induced apoptosis. Because the Ras/MAPK pathway has been shown to promote apoptosis in the germline, we are now examining the status of activated MPK-1/ERK in ccm-3 mutant germlines. CCM-3 physically interacts with the germinal center kinase III (GCK-III) family of proteins to negatively regulate ERK activation and apoptosis in mammals. Ablation of the sole GCK-III gene in the worm, gck-1, also results in defective oocyte development that resembles ccm-3 mutants. We hypothesize that CCM-3 and its binding partner GCK-1 are required for proper growth and survival of oocytes.

Affiliation:
- DEVELOPMENTAL AND STEM CELL BIOLOGY DEPARTMENT, THE HOSPITAL FOR SICK CHILDREN, TORONTO, ONTARIO, M5G 1X8 Canada