Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.
The neural-related genes Sox2, Pax6, Otx2, and Rax have been associated with severe ocular malformations such as anophthalmia and microphthalmia, but it remains unclear as to how these genes are linked functionally. We analyzed the upstream signaling of Xenopus Rax (also known as Rx1) and identified the Otx2 and Sox2 proteins as direct upstream regulators of Rax. We revealed that endogenous Otx2 and Sox2 proteins bound to the conserved noncoding sequence (CNS1) located approximately 2 kb upstream of the Rax promoter. This sequence is conserved among vertebrates and is required for potent transcriptional activity. Reporter assays showed that Otx2 and Sox2 synergistically activated transcription via CNS1. Furthermore, the Otx2 and Sox2 proteins physically interacted with each other, and this interaction was affected by the Sox2-missense mutations identified in these ocular disorders. These results demonstrate that the direct interaction and interdependence between the Otx2 and Sox2 proteins coordinate Rax expression in eye development, providing molecular linkages among the genes responsible for ocular malformation.
Danno
Hiroki
H
Department of Life Sciences (Biology), Graduate School of Arts and Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.
Michiue
Tatsuo
T
Hitachi
Keisuke
K
Yukita
Akira
A
Ishiura
Shoichi
S
Asashima
Makoto
M
D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D005124:Eye Abnormalities / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D024002:HMGB Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D051857:Otx Transcription Factors / Q000502:physiology*; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D029867:Xenopus Proteins / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis
D004268:DNA-Binding Proteins; D005136:Eye Proteins; D024002:HMGB Proteins; D051857:Otx Transcription Factors; C497661:Otx2 protein, Xenopus; C524416:Rax protein, Xenopus; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D029867:Xenopus Proteins; C527781:sox2 protein, Xenopus