Luhmann Ulrich F O, Neidhardt John, Kloeckener-Gruissem Barbara, Schäfer Nikolaus F, Glaus Esther, Feil Silke, Berger Wolfgang
Division of Medical Molecular Genetics & Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland.
Eur J Neurosci. 2008 May;27(10):2619-28. doi: 10.1111/j.1460-9568.2008.06237.x.
X-linked Norrie disease, familial exudative vitreoretinopathy (FEVR), Coat's disease and retinopathy of prematurity are severe human eye diseases and can all be caused by mutations in the Norrie disease pseudoglioma gene. They all show vascular defects and characteristic features of retinal hypoxia. Only Norrie disease displays additional neurological symptoms, which are sensorineural hearing loss and mental retardation. In the present study, we analysed transcript levels of the ligand Norrin (Ndph) and its two receptors Frizzled-4 (Fzd4) and LDL-related protein receptor 5 (Lrp5) in six different brain regions (cerebellum, cortex, hippocampus, olfactory bulb, pituitary and brain stem) of 6- to 8-month-old wild-type and Ndph knockout mice by quantitative real-time PCR. No effect of the Ndph knockout allele on Fzd4 or Lrp5 receptor expression was found. Furthermore, no alterations of the transcript levels of three hypoxia-regulated angiogenic factors (Vegfa, Itgrb3 and Tie1) were observed in the absence of Norrin. Interestingly, we identified significant differences in Ndph, Fzd4 and Lrp5 transcript levels in brain regions of wild-type mice and observed highest expression of Norrin and frizzled-4 in cerebellum. Transcript analyses were correlated with morphological data obtained from cerebellum and immunohistochemical studies of blood vessels in different brain regions. Vessel density was reduced in the cerebellum of Ndph knockout mice but the number of Purkinje and granular cells was not altered. This provides the first description of a brain phenotype in Ndph knockout mice, which will help to elucidate the role of Norrin in the brain.
X连锁诺里病、家族性渗出性玻璃体视网膜病变（FEVR）、科茨病和早产儿视网膜病变都是严重的人类眼部疾病，并且都可能由诺里病假胶质瘤基因突变引起。它们都表现出血管缺陷和视网膜缺氧的特征。只有诺里病表现出额外的神经症状，即感音神经性听力损失和智力迟钝。在本研究中，我们通过定量实时PCR分析了6至8月龄野生型和Ndph基因敲除小鼠的六个不同脑区（小脑、皮质、海马、嗅球、垂体和脑干）中配体诺林（Ndph）及其两个受体卷曲蛋白4（Fzd4）和低密度脂蛋白相关蛋白受体5（Lrp5）的转录水平。未发现Ndph基因敲除等位基因对Fzd4或Lrp5受体表达有影响。此外，在没有诺林的情况下，未观察到三种缺氧调节血管生成因子（Vegfa、Itgrb3和Tie1）转录水平的改变。有趣的是，我们发现野生型小鼠脑区中Ndph、Fzd4和Lrp5转录水平存在显著差异，并且在小脑中观察到诺林和卷曲蛋白4的表达最高。转录分析与从小脑获得的形态学数据以及不同脑区血管的免疫组织化学研究相关。Ndph基因敲除小鼠小脑中的血管密度降低，但浦肯野细胞和颗粒细胞的数量没有改变。这首次描述了Ndph基因敲除小鼠的脑表型，这将有助于阐明诺林在脑中的作用。
