title: An essential role for RAX homeoprotein and NOTCH-HES signaling in Otx2 expression in embryonic retinal photoreceptor cell fate determination.
abstract: The molecular mechanisms underlying cell fate determination from common progenitors in the vertebrate CNS remain elusive. We previously reported that the OTX2 homeoprotein regulates retinal photoreceptor cell fate determination. While Otx2 transactivation is a pivotal process for photoreceptor cell fate determination, its transactivation mechanism in the retina is unknown. Here, we identified an evolutionarily conserved Otx2 enhancer of ∼500 bp, named embryonic enhancer locus for photoreceptor Otx2 transcription (EELPOT), which can recapitulate initial Otx2 expression in the embryonic mouse retina. We found that the RAX homeoprotein interacts with EELPOT to transactivate Otx2, mainly in the final cell cycle of retinal progenitors. Conditional inactivation of Rax results in downregulation of Otx2 expression in vivo. We also showed that NOTCH-HES signaling negatively regulates EELPOT to suppress Otx2 expression. These results suggest that the integrated activity of cell-intrinsic and -extrinsic factors on EELPOT underlies the molecular basis of photoreceptor cell fate determination in the embryonic retina.
authors.affiliation: Department of Developmental Biology, Osaka Bioscience Institute, Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Osaka 565-0874, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Muranishi
authors.forename: Koji
authors.initials: K
authors.lastname: Terada
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Inoue
authors.forename: Kimiko
authors.initials: K
authors.lastname: Katoh
authors.forename: Toshinori
authors.initials: T
authors.lastname: Tsujii
authors.forename: Rikako
authors.initials: R
authors.lastname: Sanuki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurokawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aizawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tamaki
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis; D009924:Organ Culture Techniques; D051857:Otx Transcription Factors / Q000378:metabolism*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; D012333:RNA, Messenger; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; C497660:Otx2 protein, mouse; C105441:Rax protein, mouse
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