title: Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice.
abstract: Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5μm (leading to a minimum feature size of approximately 25μm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high-resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases.
authors: Lab of Cardiovascular Signaling, Centenary Institute, Sydney, NSW, 2050, Australia.|Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, 2050, Australia.
authors: Jaesung P
authors: JP
authors: Choi
authors: Australian Centre for Microscopy & Microanalysis, University of Sydney, Sydney, NSW, 2006, Australia.
authors: Matthew
authors: M
authors: Foley
authors: Department of Pharmacology and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, 19104.
authors: Zinan
authors: Z
authors: Zhou
authors: Lab of Cardiovascular Signaling, Centenary Institute, Sydney, NSW, 2050, Australia.
authors: Weng-Yew
authors: WY
authors: Wong
authors: Australian Centre for Microscopy & Microanalysis, University of Sydney, Sydney, NSW, 2006, Australia.
authors: Naveena
authors: N
authors: Gokoolparsadh
authors: Division of Cell Signaling and Immunology, University of Dundee, Dundee, DD1 5EH, United Kingdom.
authors: J Simon C
authors: JS
authors: Arthur
authors: Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, UT, 84112, United States of America.
authors: Dean Y
authors: DY
authors: Li
authors: Lab of Cardiovascular Signaling, Centenary Institute, Sydney, NSW, 2050, Australia.|Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, 2050, Australia.
authors: Xiangjian
authors: X
authors: Zheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D048748:MAP Kinase Kinase Kinase 3 / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D008844:Micrognathism / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D012272:Ribs / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000378:metabolism; D055114:X-Ray Microtomography
chemical_list: D008840:Microfilament Proteins; C480498:osmosensing scaffold for MEKK3 protein, mouse; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse