期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 31, 期 3, 页码 411-422出版社
WILEY
DOI: 10.1111/pcmr.12676
关键词
age-related macular degeneration; alternative splicing; MITF; pigment cell; retinal pigment epithelium
资金
- National Natural Science Foundation of China [81570892, 81600748, 81770946]
- Medical Scientific Research Foundation of Zhejiang Province, China [2016KYB205, 2017KY487]
- Wenzhou public welfare project [Y20160054]
- Zhejiang Provincial NSF [LQ16C070001]
- Research Grant of Wenzhou Medical University
- Research Grant of Wenzhou Medical University Eye Hospital [KYQD151211, KYQD130301, YNZD201605]
Vertebrate eye development and homoeostasis critically depend on the regulation of proliferation of cells forming the retinal pigment epithelium (RPE). Previous results indicated that the death-associated protein like-1 DAPL1 cell autonomously suppresses RPE proliferation in vivo and in vitro. Here, we show in human RPE cell lines that the pigment cell transcription factor MITF regulates RPE cell proliferation by upregulating DAPL1 expression. DAPL1 regulation by MITE is, however, mediated predominantly by (-) MITF, one of two alternative splice isoforms of MITF that lacks six residues located upstream of the DNA-binding basic domain. Furthermore, we find that the regulation of DAPL1 by MITE is indirect in that (-) MITE stimulates the transcription of Musashi homolog-2 (MS12), which negatively regulates the processing of the anti-DAPL1 microRNA miR-7. Our results provide molecular insights into the regulation of RPE cell proliferation and quiescence and may help us understand the mechanisms of normal RPE maintenance and of eye diseases associated with either RPE hyperproliferation or the lack of regenerative proliferation.
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