Cerebral cavernous malformations (CCM) are disorders that cause biological tubes in the brain (i.e., veins and capillaries) to become deformed and leak blood, leading to symptoms that can range from mild headaches to hemorrhagic stroke. This rare disease can occur in people sporadically by unknown mechanisms or by inheritance of mutations in one of three genes (CCM1, CCM2 or CCM3). Patients with mutations in the CCM3 gene have the earliest disease onset (often in childhood) and suffer the greatest lesion burden compared with patients who inherit mutations in CCM1 or CCM2. The mechanism by which CCM3 maintains the integrity of biological tubes is not understood and there are currently no treatments for CCM patients, other than invasive neurosurgery. In this paper, Brent Derry's lab showed that CCM3 functions to maintain the integrity of the C. elegans germline by promoting endocytic recycling of cell surface receptors and membrane to the cytokinetic furrow of dividing cells. The also show that CCM-3, and its associated striatin interacting phosphatase and kinase (STRIPAK) complex, coordinates organization of anillin and non-muscle myosin to generate contractile forces necessary for cytokinesis and assembly of cells into biological tubes. By combining the powerful genetics and cell biology of C. elegans with proteomics methods in collaboration with Molecular Genetics professors Mike Moran and Anne-Claude Gingras they show that association of CCM-3 with its binding partners striatin and the germinal centre kinase GCK-1, dictates its subcellular localization as well as the proper positioning of polarity proteins in dividing embryonic cells and in the developing germline. This work provides new insights into the normal biological functions of CC3/STRIPAK during development that should uncover effective therapeutic targets for treating CCM patients. Towards this goal Derry is also collaborating with Peter Roy (CCBR) to identify small molecules that reverse the germline defects of ccm-3 mutants. This work was supported by grants from the CIHR and a donation from Angioma Alliance Canada.
CCM-3 Promotes C. elegans Germline Development by Regulating Vesicle Trafficking Cytokinesis and Polarity