title: Microphthalmia-associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression.
abstract: The retinal pigment epithelium (RPE) plays a fundamental role in maintaining visual function and dedifferentiation of RPE contributes to the pathophysiology of several ocular diseases. To identify microRNAs (miRNAs) that may be involved in RPE differentiation, we compared the miRNA expression profiles of differentiated primary human fetal RPE (hfRPE) cells to dedifferentiated hfRPE cells. We found that miR-204/211, the two most highly expressed miRNAs in the RPE, were significantly down-regulated in dedifferentiated hfRPE cells. Importantly, transfection of pre-miR-204/211 into hfRPE cells promoted differentiation whereas adding miR-204/211 inhibitors led to their dedifferentiation. Microphthalmia-associated transcription factor (MITF) is a key regulator of RPE differentiation that was also down-regulated in dedifferentiated hfRPE cells. MITF knockdown decreased miR-204/211 expression and caused hfRPE dedifferentiation. Significantly, co-transfection of MITF siRNA with pre-miR-204/211 rescued RPE phenotype. Collectively, our data show that miR-204/211 promote RPE differentiation, suggesting that miR-204/211-based therapeutics may be effective treatments for diseases that involve RPE dedifferentiation such as proliferative vitreoretinopathy.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Adijanto
authors.forename: John J
authors.initials: JJ
authors.lastname: Castorino
authors.forename: Zi-Xuan
authors.initials: ZX
authors.lastname: Wang
authors.forename: Arvydas
authors.initials: A
authors.lastname: Maminishkis
authors.forename: Gerald B
authors.initials: GB
authors.lastname: Grunwald
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Philp
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism*; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics / Q000378:metabolism / Q000628:therapy
chemical_list: C549404:MIRN204 microRNA, human; C549405:MIRN211 microRNA, human; C497234:MITF protein, human; D035683:MicroRNAs; D051739:Microphthalmia-Associated Transcription Factor