Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice.
Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice.
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DOI：
10.1371/journal.pone.0160833
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Choi JP;Foley M;Zhou Z;Wong WY;Gokoolparsadh N;Arthur JS;Li DY;Zheng X
CCM1（又名KRIT1）、CCM2或CCM3（又名PDCD10）基因突变导致人类脑海绵状血管瘤。通过在出生后的动物中删除CCM基因，建立了CCM疾病的小鼠模型。这些小鼠模型为研究CCM疾病的分子机制和治疗方法提供了宝贵的工具。然而，由于缺乏准确和定量的方法来评估病变负担和进展，这些动物模型的全部价值受到限制。在本研究中，我们建立了一种精细、详细的对比增强x射线微ct方法来测量小鼠大脑CCM病变负荷。由于本研究使用9.5μm的体素尺寸（最小特征尺寸约为25μm），因此足以全面准确地测量CCM病变体积和数量，并提供小鼠大脑CCM病变的高分辨率三维映射。通过这种方法，我们发现新生儿内皮细胞中Ccm1或Ccm2的缺失导致小鼠后脑CCM病变的总量和数量相似。这种定量方法也证明了同时删除Mekk3的一个等位基因可以挽救CCM病变。该方法将提高所建立的小鼠模型在研究CCM及其他脑血管疾病的分子基础和潜在治疗方法方面的价值。
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.