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Proc Natl Acad Sci U S A April 8, 2008; 105 (14): 5408-13.

Molecular links among the causative genes for ocular malformation: Otx2 and Sox2 coregulate Rax expression.

Danno H , Michiue T , Hitachi K , Yukita A , Ishiura S , Asashima M .

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.

PubMed ID: 18385377
PMC ID: PMC2291098
Article link: Proc Natl Acad Sci U S A

Species referenced: Xenopus
Genes referenced: myc otx2 pax6 prkra rax sox2

Article Images: [+] show captions
References [+] :
Adler, Molecular mechanisms of optic vesicle development: complexities, ambiguities and controversies. 2007, Pubmed