DAPL1, a susceptibility locus for age-related macular degeneration, acts as a novel suppressor of cell proliferation in the retinal pigment epithelium.
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.
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.
Xiaoyin
X
Ma
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
Huirong
H
Li
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
Yipin
Y
Wang
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.
Jing
J
Wang
State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou 325003, China.
Qinxiang
Q
Zheng
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
Jiajia
J
Hua
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
Juan
J
Yang
Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, China.
Li
L
Pan
State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou 325003, China.
Fan
F
Lu
State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou 325003, China.
Jia
J
Qu
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.
Ling
L
Hou
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D004198:Disease Susceptibility; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D012160:Retina / Q000166:cytology / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000378:metabolism; D012307:Risk Factors
C000606731:DAPL1 protein, human; D008565:Membrane Proteins