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.


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


  • 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

Grant support

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.