Gardiner Kristin L, Downs Louise, Berta-Antalics Agnes I, Santana Evelyn, Aguirre Gustavo D, Genini Sem
Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey Street, Philadelphia, PA, 19104, USA.
Augenklinik Uniklinik Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
BMC Genomics. 2016 Mar 11;17:221. doi: 10.1186/s12864-016-2477-9.
Mitotic terminally differentiated photoreceptors (PRs) are observed in early retinal degeneration (erd), an inherited canine retinal disease driven by mutations in the NDR kinase STK38L (NDR2).
We demonstrate that a similar proliferative response, but of lower magnitude, occurs in two other early onset disease models, X-linked progressive retinal atrophy 2 (xlpra2) and rod cone dysplasia 1 (rcd1). Proliferating cells are rod PRs, and not microglia or Müller cells. Expression of the cell cycle related genes RB1 and E2F1 as well as CDK2,4,6 was up-regulated, but changes were mutation-specific. Changes in cyclin expression differed across all genes, diseases and time points analyzed, although CCNA1 and CCNE1 expression increased with age in the three models suggesting that there is a dysregulation of cell cycle gene expression in all three diseases. Unique to erd, however, are mutation-specific changes in the expression of NDR kinases and Hippo signaling members with increased expression of MOB1 and LATS1 in the newly generated hybrid rod/S-cones.
Our data raise the intriguing possibility that terminally differentiated normal PRs are kept from dividing by NDR2-MOB1 interaction. Furthermore, they provide the framework for the selection of candidate genes for further investigation as potential targets of therapy.
在早期视网膜变性（erd）中观察到有丝分裂终末分化的光感受器（PRs），erd是一种由NDR激酶STK38L（NDR2）突变驱动的遗传性犬视网膜疾病。
我们证明，在另外两种早发性疾病模型，即X连锁进行性视网膜萎缩2（xlpra2）和视锥视杆细胞营养不良1（rcd1）中，也会发生类似的增殖反应，但程度较低。增殖细胞是视杆PRs，而非小胶质细胞或穆勒细胞。细胞周期相关基因RB1、E2F1以及CDK2、4、6的表达上调，但变化具有突变特异性。在分析的所有基因、疾病和时间点中，细胞周期蛋白表达的变化各不相同，不过在这三种模型中，CCNA1和CCNE1的表达均随年龄增加，这表明在所有这三种疾病中细胞周期基因表达均失调。然而，erd独有的是NDR激酶和Hippo信号通路成员表达的突变特异性变化，新生成的杂交视杆/S - 视锥细胞中MOB1和LATS1表达增加。
我们的数据提出了一个有趣的可能性，即终末分化的正常PRs通过NDR2 - MOB1相互作用而被阻止分裂。此外，它们为选择候选基因作为潜在治疗靶点进行进一步研究提供了框架。
