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

ABSTRACT: 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.

SUBMITTER: Danno H

PROVIDER: S-EPMC2291098 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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

Danno Hiroki H Michiue Tatsuo T Hitachi Keisuke K Yukita Akira A Ishiura Shoichi S Asashima Makoto M

Proceedings of the National Academy of Sciences of the United States of America 20080402 14

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 upstrea ...[more]

PMID: 18385377

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Project description:BackgroundTreatment of Chiari malformation can include suboccipital decompression with resection of one cerebellar tonsil. Its effects on ocular motor and cerebellar function have not yet been systematically examined.ObjectiveTo investigate whether decompression, including resection of one cerebellar tonsil, leads to ocular motor, vestibular, or cerebellar deficits.Patients and methodsTen patients with Chiari malformation type 1 were systematically examined before and after (1 week and 3 months) suboccipital decompression with unilateral tonsillectomy. The work-up included a neurological and neuro-ophthalmological examination, vestibular function, posturography, and subjective scales. Cerebellar function was evaluated by ataxia rating scales.ResultsDecompression led to a major subjective improvement 3 months after surgery, especially regarding headache (5/5 patients), hyp-/dysesthesia (5/5 patients), ataxia of the upper limbs (4/5 patients), and paresis of the triceps and interosseal muscles (2/2 patients). Ocular motor disturbances before decompression were detected in 50% of the patients. These symptoms improved after surgery, but five patients had new persisting mild ocular motor deficits 3 months after decompression with unilateral tonsillectomy (i.e., smooth pursuit deficits, horizontally gaze-evoked nystagmus, rebound, and downbeat nystagmus) without any subjective complaints. Impaired vestibular (horizontal canal, saccular, and utricular) function improved in five of seven patients with impaired function before surgery. Posturographic measurements after surgery did not change significantly.ConclusionDecompression, including resection of one cerebellar tonsil, leads to an effective relief of patients' preoperative complaints. It is a safe procedure when performed with the help of intraoperative electrophysiological monitoring, although mild ocular motor dysfunctions were seen in half of the patients, which were fortunately asymptomatic.

Dataset Information

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

Publications

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

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