Regulation of cell proliferation in the retinal pigment epithelium: Differential regulation of the death‐associated protein like‐1 DAPL1 by alternative MITF splice forms

Summary 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 vitr...

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Published inPigment cell and melanoma research Vol. 31; no. 3; pp. 411 - 422
Main Authors Ma, Xiaoyin, Hua, Jiajia, Zheng, Guoxiao, Li, Fang, Rao, Chunbao, Li, Huirong, Wang, Jing, Pan, Li, Hou, Ling
Format Journal Article
LanguageEnglish
Published England Wiley Subscription Services, Inc 01.05.2018
Subjects
age‐related macular degeneration
Alternative splicing
Cell growth
Cell lines
Cell proliferation
Deoxyribonucleic acid
DNA
Epithelium
Eye diseases
Homology
Isoforms
Kinases
miRNA
MITF
pigment cell
Retina
Retinal pigment epithelium
Ribonucleic acid
RNA
MITF
pigment cell
retinal pigment epithelium
alternative splicing
age-related macular degeneration
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Summary:Summary 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 MITF 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 MITF is indirect in that (−) MITF stimulates the transcription of Musashi homolog‐2 (MSI2), 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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ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12676