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

• Published in: Pigment cell and melanoma research 2018-05, Vol.31 (3), p.411-422
• Main Authors: Ma, Xiaoyin, Hua, Jiajia, Zheng, Guoxiao, Li, Fang, Rao, Chunbao, Li, Huirong, Wang, Jing, Pan, Li, Hou, Ling
• Format: Article
• Language: English
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12676

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 DAPL 1 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 DAPL 1 expression. DAPL 1 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 DAPL 1 by MITF is indirect in that (−) MITF stimulates the transcription of Musashi homolog‐2 ( MSI 2 ), which negatively regulates the processing of the anti‐ DAPL 1 micro RNA 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.