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

Pigment Cell Melanoma Res. 2018 May;31(3):411-422. doi: 10.1111/pcmr.12676. Epub 2017 Dec 9.

Abstract

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.

Keywords: MITF; age-related macular degeneration; alternative splicing; pigment cell; retinal pigment epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Cell Line
  • Cell Proliferation / physiology*
  • Humans
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Microphthalmia-Associated Transcription Factor / genetics
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / metabolism*
  • Transcription, Genetic / physiology*

Substances

  • DAPL1 protein, human
  • MITF protein, human
  • MSI2 protein, human
  • Membrane Proteins
  • Microphthalmia-Associated Transcription Factor
  • RNA-Binding Proteins