title: Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease.
abstract: Cerebral cavernous malformations (CCMs) are vascular anomalies of the central nervous system that arise due to mutations in genes encoding three unrelated proteins: CCM1 (KRIT1); CCM2 (Malcavernin/OSM) and CCM3 (PDCD10). Both biochemical and mutant studies suggest that CCM1 and CCM2 act as part of a physical complex to regulate vascular morphogenesis and integrity. In contrast, mouse Ccm3 mutant and in vitro cell culture data suggests an independent role for Ccm3. In this study, we sought to use the zebrafish model system to examine for the first time the role of ccm3 in cranial vessel development. We report that inhibition of zebrafish ccm3a/b causes heart and circulation defects distinct from those seen in ccm1 (santa) and ccm2 (valentine) mutants, and leads to a striking dilation and mispatterning of cranial vessels reminiscent of the human disease pathology. ccm3, but not ccm2, defects can be rescued upon overexpression of stk25b, a GCKIII kinase previously shown to interact with CCM3. Morpholino knockdown of the GCKIII gene stk25b results in heart and vasculature defects similar to those seen in ccm3 morphants. Finally, additional loss of ccm3 in ccm2 mutants leads to a synergistic increase in cranial vessel dilation. These results support a model in which CCM3 plays a role distinct from CCM1/2 in CCM pathogenesis, and acts via GCKIII activity to regulate cranial vasculature integrity and development. CCM3/GCKIII activity provides a novel therapeutic target for CCMs, as well as for the modulation of vascular permeability.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Bilge
authors.initials: B
authors.lastname: Yoruk
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Gillers
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism*; D020785:Central Nervous System Vascular Malformations / Q000235:genetics* / Q000473:pathology; D055785:Gene Knockdown Techniques; D000081410:Germinal Center Kinases; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics*; D060172:Morpholinos / Q000235:genetics; D009124:Muscle Proteins; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000081410:Germinal Center Kinases; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D060172:Morpholinos; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D029961:Zebrafish Proteins; C514537:krit1 protein, zebrafish; C542753:pdcd10a protein, zebrafish; D017346:Protein Serine-Threonine Kinases