title: PAX6 regulates melanogenesis in the retinal pigmented epithelium through feed-forward regulatory interactions with MITF.
abstract: During organogenesis, PAX6 is required for establishment of various progenitor subtypes within the central nervous system, eye and pancreas. PAX6 expression is maintained in a variety of cell types within each organ, although its role in each lineage and how it acquires cell-specific activity remain elusive. Herein, we aimed to determine the roles and the hierarchical organization of the PAX6-dependent gene regulatory network during the differentiation of the retinal pigmented epithelium (RPE). Somatic mutagenesis of Pax6 in the differentiating RPE revealed that PAX6 functions in a feed-forward regulatory loop with MITF during onset of melanogenesis. PAX6 both controls the expression of an RPE isoform of Mitf and synergizes with MITF to activate expression of genes involved in pigment biogenesis. This study exemplifies how one kernel gene pivotal in organ formation accomplishes a lineage-specific role during terminal differentiation of a single lineage.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shaul
authors.initials: S
authors.lastname: Raviv
authors.affiliation: Unit on Ocular and Stem Cell Translational Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kapil
authors.initials: K
authors.lastname: Bharti
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Rencus-Lazar
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yamit
authors.initials: Y
authors.lastname: Cohen-Tayar
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schyr
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Naveh
authors.initials: N
authors.lastname: Evantal
authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Meshorer
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Alona
authors.initials: A
authors.lastname: Zilberberg
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy & Department of Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Idelson
authors.affiliation: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy & Department of Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Reubinoff
authors.affiliation: Wilmer Ophthalmological Institute, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Grebe
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rina
authors.initials: R
authors.lastname: Rosin-Arbesfeld
authors.affiliation: Department of Cellular Biology, The University of Georgia, Athens, Georgia, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Lauderdale
authors.affiliation: Wilmer Ophthalmological Institute, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lutty
authors.affiliation: Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, United States of America.
authors.forename: Heinz
authors.initials: H
authors.lastname: Arnheiter
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D005136:Eye Proteins / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D010858:Pigmentation / Q000235:genetics; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000254:growth & development / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins