van de Pavert Serge A, Sanz Alicia Sanz, Aartsen Wendy M, Vos Rogier M, Versteeg Inge, Beck Susanne C, Klooster Jan, Seeliger Mathias W, Wijnholds Jan
Department of Neuromedical Genetics, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences , Amsterdam, The Netherlands.
Glia. 2007 Nov 1;55(14):1486-97. doi: 10.1002/glia.20561.
Mutations in the human Crumbs homologue-1 (CRB1) gene cause retinal blinding diseases, such as Leber congenital amaurosis and retinitis pigmentosa. In the previous studies we have shown that Crb1 resides in retinal Müller glia cells and that loss of Crb1 results in retinal degeneration (particularly in the inferior temporal quadrant of the mouse eye). Degeneration is increased by exposure to white light. Here, we studied the role of light and aging to gain a better understanding of the factors involved in the progress of retinal disease. Our data reveal that light is neither sufficient nor required to induce retinal disorganization and degeneration in young Crb1(-/-) mutant mice, suggesting that it rather modulates the retinal phenotype. Gene expression profiling showed that expression of five genes is altered in light-exposed Crb1(-/-) mutant retinas. Three of the five genes are involved in chromosome stabilization (Pituitary tumor transforming gene 1 or Pttg1, Establishment of cohesion 1 homolog 1 or Esco1, and a gene similar to histone H2B). In aged retinas, degeneration of photoreceptors, inner retinal neurons, and retinal pigment epithelium was practically limited to the inferior temporal quadrant. Loss of Crb1 in Müller glia cells resulted in an irregular number and size of their apical villi. We propose that Crb1 is required to regulate number and size of these Müller glia cell villi. The subsequent loss of retinal integrity resulted in neovascularization, in which blood vessels of the choroid protruded into the neural retina.
人类同源性E3泛素蛋白连接酶1（CRB1）基因的突变会引发视网膜致盲疾病，如莱伯先天性黑蒙和视网膜色素变性。在之前的研究中，我们已经表明Crb1存在于视网膜穆勒神经胶质细胞中，并且Crb1的缺失会导致视网膜变性（特别是在小鼠眼睛的颞下象限）。暴露于白光会加剧这种变性。在这里，我们研究了光照和衰老的作用，以更好地了解视网膜疾病进展过程中的相关因素。我们的数据显示，光照对于诱导年轻的Crb1（-/-）突变小鼠的视网膜紊乱和变性既不是充分条件也不是必要条件，这表明光照更像是在调节视网膜表型。基因表达谱分析表明，在暴露于光照的Crb1（-/-）突变小鼠视网膜中，有五个基因的表达发生了改变。这五个基因中的三个与染色体稳定有关（垂体肿瘤转化基因1或Pttg1、黏连蛋白建立同源物1或Esco1以及一个与组蛋白H2B相似的基因）。在老年视网膜中，光感受器、视网膜内层神经元和视网膜色素上皮的变性实际上仅限于颞下象限。穆勒神经胶质细胞中Crb1的缺失导致其顶端绒毛的数量和大小不规则。我们认为，Crb1是调节这些穆勒神经胶质细胞绒毛数量和大小所必需的。随后视网膜完整性的丧失导致了新生血管形成，脉络膜血管由此突入神经视网膜。
