OTX2 activates the molecular network underlying retina pigment epithelium differentiation.
The retina pigment epithelium (RPE) is fundamental for the development and function of the vertebrate eye. Molecularly, the presumptive RPE can be identified by the early expression of two transcription factors, Mitf and Otx. In mice deficient for either gene, RPE development is impaired with loss of melanogenic gene expression, raising the possibility that in the eye OTX proteins operate either in a feedback loop or in cooperation with MITF for the control of RPE-specific gene expression. Here we show that Otx2 induces a pigmented phenotype when overexpressed in avian neural retina cells. In addition, OTX2 binds specifically to a bicoid motif present in the promoter regions of three Mitf target genes, QNR71, TRP-1, and tyrosinase, leading to their transactivation. OTX2 and MITF co-localize in the nuclei of RPE cells and physically interact, and their co-expression results in a cooperative activation of QNR71 and tyrosinase promoters. Collectively, these data suggest that both transcription factors operate at the same hierarchical level to establish the identity of the RPE.
Martínez-Morales
Juan Ramón
JR
Instituto Cajal, Consejo Superior de Investigaciones Científicas, Dr. Arce 37, Madrid 28002, Spain.
Dolez
Vincent
V
Rodrigo
Isabel
I
Zaccarini
Raffaella
R
Leconte
Laurence
L
Bovolenta
Paola
P
Saule
Simon
S
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D051857:Otx Transcription Factors; D010088:Oxidoreductases; D010641:Phenotype; D010857:Pigment Epithelium of Eye / Q000166:cytology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics; D011784:Quail; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D011506:Proteins; C100584:QNR-71 protein, Coturnix japonica; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D010088:Oxidoreductases; D008156:Luciferases; C079621:Tyrp1 protein, mouse; C064056:tyrosinase-related protein-1; D014442:Monophenol Monooxygenase; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase