Ma Xiaoyin, Li Huirong, Wang Yipin, Wang Jing, Zheng Qinxiang, Hua Jiajia, Yang Juan, Pan Li, Lu Fan, Qu Jia, Hou Ling
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou 325003, China.
Hum Mol Genet. 2017 May 1;26(9):1612-1621. doi: 10.1093/hmg/ddx063.
The retinal pigment epithelium (RPE) forms a monolayer at the back of the vertebrate eye and is fundamental to retinal function and homoeostasis. During early development, RPE cells undergo rapid proliferation, but in the adult, they remain normally nonproliferative throughout life. Nevertheless, under pathological conditions such as in proliferative vitreoretinopathy or after retinal ablation, mature RPE cells can re-enter the cell cycle and form nodules or multiple cell layers. Here we show that Dapl1, whose human homolog represents a susceptibility locus for age-related macular degeneration (AMD), is highly up-regulated in quiescent but not proliferating RPE cells and that experimental overexpression of DAPL1 in proliferating RPE cells inhibits their proliferation. Consistent with this observation, the percent of Ki67-positive cells is significantly higher in E11.5 Dapl1 knockout mouse embryos compared to age-matched controls. In adult Dapl1-/- mice, which survive without showing any overt pathology, RPE overgrowth leads to multiple cell layers and/or cellular nodules. The antiproliferative effect of DAPL1 is associated with an increase in CDKN1A protein levels. Reduction of CDKN1A by siRNA in DAPL1-overexpressing RPE cells in vitro partially restores cell proliferation. Hence, we show that DAPL1 is a novel regulator of RPE cell proliferation that is important for the maintenance of the RPE as a monolayer. The findings suggest that DAPL1 dysregulation may be involved in abnormal RPE-related proliferative diseases and corresponding retinal dysfunctions in humans.
视网膜色素上皮（RPE）在脊椎动物眼球后部形成一层细胞，对视网膜功能和体内平衡至关重要。在早期发育过程中，RPE细胞经历快速增殖，但在成年后，它们在一生中通常保持非增殖状态。然而，在诸如增殖性玻璃体视网膜病变或视网膜切除术后等病理条件下，成熟的RPE细胞可重新进入细胞周期并形成结节或多层细胞。我们在此表明，Dapl1（其人类同源物是年龄相关性黄斑变性（AMD）的一个易感基因座）在静止而非增殖的RPE细胞中高度上调，并且在增殖的RPE细胞中实验性过表达DAPL1可抑制其增殖。与这一观察结果一致，与年龄匹配的对照相比，E11.5 Dapl1基因敲除小鼠胚胎中Ki67阳性细胞的百分比显著更高。在成年Dapl1-/-小鼠中，它们存活且未表现出任何明显的病理状况，但RPE过度生长会导致多层细胞和/或细胞结节。DAPL1的抗增殖作用与CDKN1A蛋白水平的增加有关。在体外过表达DAPL1的RPE细胞中通过siRNA降低CDKN1A可部分恢复细胞增殖。因此，我们表明DAPL1是RPE细胞增殖的一种新型调节因子，对维持RPE单层细胞状态很重要。这些发现表明，DAPL1失调可能与人类异常的RPE相关增殖性疾病及相应的视网膜功能障碍有关。
