PAX6 regulates melanogenesis in the retinal pigmented epithelium through feed-forward regulatory interactions with MITF

Shaul Raviv; Kapil Bharti; Sigal Rencus-Lazar; Yamit Cohen-Tayar; Rachel Schyr; Naveh Evantal; Eran Meshorer; Alona Zilberberg; Maria Idelson; Benjamin Reubinoff; Rhonda Grebe; Rina Rosin-Arbesfeld; James Lauderdale; Gerard Lutty; Heinz Arnheiter; Ruth Ashery-Padan

doi:10.1371/journal.pgen.1004360

PAX6 regulates melanogenesis in the retinal pigmented epithelium through feed-forward regulatory interactions with MITF

PLoS Genet. 2014 May 29;10(5):e1004360. doi: 10.1371/journal.pgen.1004360. eCollection 2014.

Authors

Shaul Raviv¹, Kapil Bharti², Sigal Rencus-Lazar¹, Yamit Cohen-Tayar¹, Rachel Schyr³, Naveh Evantal³, Eran Meshorer³, Alona Zilberberg⁴, Maria Idelson⁵, Benjamin Reubinoff⁵, Rhonda Grebe⁶, Rina Rosin-Arbesfeld⁴, James Lauderdale⁷, Gerard Lutty⁶, Heinz Arnheiter⁸, Ruth Ashery-Padan¹

Affiliations

¹ Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
² Unit on Ocular and Stem Cell Translational Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
³ Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁴ Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
⁵ 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.
⁶ Wilmer Ophthalmological Institute, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States of America.
⁷ Department of Cellular Biology, The University of Georgia, Athens, Georgia, United States of America.
⁸ Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / genetics*
Eye Proteins / biosynthesis*
Eye Proteins / genetics
Gene Expression Regulation, Developmental
Homeodomain Proteins / biosynthesis*
Homeodomain Proteins / genetics
Mice
Microphthalmia-Associated Transcription Factor / biosynthesis
Microphthalmia-Associated Transcription Factor / genetics*
Organogenesis / genetics*
PAX6 Transcription Factor
Paired Box Transcription Factors / biosynthesis*
Paired Box Transcription Factors / genetics
Pigmentation / genetics
Promoter Regions, Genetic
Repressor Proteins / biosynthesis*
Repressor Proteins / genetics
Retinal Pigment Epithelium / growth & development
Retinal Pigment Epithelium / metabolism

Substances

Eye Proteins
Homeodomain Proteins
Microphthalmia-Associated Transcription Factor
Mitf protein, mouse
PAX6 Transcription Factor
PAX6 protein, human
Paired Box Transcription Factors
Pax6 protein, mouse
Repressor Proteins

Grants and funding

Research in RA-P's laboratory is supported by the German Israeli Foundation (I-1128-156.1/201), Israel Science Foundation (610/10), Israel Science Foundation-Morasha (1372/11), Ministry of Science and Technology Israel, and the Ministry of Foreign Affairs Italy (3-8828), Bright Focus Foundation (M2013065) and Maratier Foundation for the Study of Blindness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.