Abstract
Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.
Highlights
Ocular coloboma arises when the embryonic choroid fissure in the ventral optic cup fails to close
We have taken advantage of the ability to titrate levels of gene expression in zebrafish to demonstrate for the first time that the transcription factor Sox11 is required to limit levels of Hedgehog (Hh) signaling during ocular development
We show that in the absence of Sox11, levels of the Sonic Hedgehog (Shh) ligand are greatly elevated, which disrupts the proper patterning of the optic stalk and optic vesicle, resulting in coloboma
Summary
Ocular coloboma arises when the embryonic choroid fissure in the ventral optic cup fails to close. Given its central role in eye development, it is unsurprising that mutations in genes encoding Hh pathway ligands (SHH) or targets (PAX2, VAX1) are associated with congenital ocular malformations in humans [6,7,8,9] These mutations account for only a minority of patients; for the majority of MAC cases, the molecular defect has yet to be identified. Because of their potency, the spatiotemporal levels of Hh ligands must be tightly regulated throughout eye development; yet, very little is known about the factors that restrict their expression during oculogenesis. Such factors would represent excellent candidate genes for human coloboma and associated ocular defects, and potentially could be used to influence Hh signaling
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