A CNS-specific hypomorphic Pdgfr-beta mutant model of diabetic retinopathy.
A CNS-specific hypomorphic Pdgfr-beta mutant model of diabetic retinopathy.
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DOI：
10.1167/iovs.12-11125
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发表时间：
2013-05-01
影响因子：
4.4
通讯作者：
Jackson IJ
中科院分区：
文献类型：
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作者：
Jadeja S;Mort RL;Keighren M;Hart AW;Joynson R;Wells S;Potter PK;Jackson IJ
在隐性ENU诱变筛选期间鉴定的小鼠突变体表现出眼部出血，导致眼眶充血，因此被命名为“红眼”。我们的目的是确定红眼的致病突变，并评估其作为糖尿病视网膜病变（DR）的模型。红眼病的致病基因突变通过单倍型作图和外显子组测序鉴定。进行葡萄糖耐量试验、详细的组织学和免疫荧光分析以及血管通透性测定，以确定红眼对葡萄糖代谢、周细胞募集以及视网膜血管系统和血视网膜屏障（BRB）发育的影响。在Pdgfrb基因内含子6的+2位鉴定出突变。我们表明，这种变化导致部分损失的正常剪接导致移码和过早终止，因此，在正常的Pdgfrb转录大幅减少。这些动物表现出局限于中枢神经系统（CNS）的周细胞募集缺陷，导致基底膜和血管图案缺陷、血管通透性受损和BRB发育异常，导致血管渗漏和视网膜神经节细胞凋亡。尽管表现出糖尿病视网膜病变的典型特征，但红眼葡萄糖耐量是正常的。Pdgfrbredeye/redeye小鼠表现出非增殖性DR的所有特征，包括视网膜神经变性。此外，CNS特异性血管表型的围产期发作否定了对动物年龄或管理其他器官中的糖尿病并发症的需要。因此，与目前使用的模型相比，它们是涉及周细胞缺陷的疾病（如DR）的更有用的模型。
A mouse mutant identified during a recessive ENU mutagenesis screen exhibited ocular haemorrhaging resulting in a blood filled orbit, and hence was named ‘redeye’. We aimed to identify the causal mutation in redeye, and evaluate it as a model for Diabetic Retinopathy (DR). The causative gene mutation in redeye was identified by haplotype mapping followed by exome sequencing. Glucose tolerance tests, detailed histological and immunofluorescence analyses, and vascular permeability assays were performed to determine the affect of redeye on glucose metabolism, pericyte recruitment and the development of the retinal vasculature and the blood retinal barrier (BRB). A mutation was identified in the Pdgfrb gene at position +2 of intron 6. We show that this change causes partial loss of normal splicing resulting in a frameshift and premature termination, and therefore a substantial reduction in normal Pdgfrb transcript. The animals exhibit defective pericyte recruitment restricted to the central nervous system (CNS) causing basement membrane and vascular patterning defects, impaired vascular permeability and aberrant BRB development, resulting in vascular leakage and retinal ganglion cell apoptosis. Despite exhibiting classical features of diabetic retinopathy redeye glucose tolerance is normal. The Pdgfrbredeye/redeye mice exhibit all of the features of non-proliferative DR including retinal neurodegeneration. In addition, the perinatal onset of the CNS-specific vascular phenotype negates the need to age animals or manage diabetic complications in other organs. Therefore they are a more useful model for diseases involving pericyte deficiencies such as DR than those currently being used.
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影响因子：
8.8
作者：
Heldin, C H;Hammacher, A;Nister, M;Westermark, B
通讯作者：
Westermark, B
影响因子：
20.3
作者：
Franco, Marcela;Roswall, Pernilla;Pietras, Kristian
通讯作者：
Pietras, Kristian
影响因子：
4.4
作者：
Hart, AW;McKie, L;Cross, SH
通讯作者：
Cross, SH
影响因子：
4.4
作者：
Feit-Leichman, RA;Kinouchi, R;Chen, DF
通讯作者：
Chen, DF
影响因子：
82.9
作者：
通讯作者：
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