title: Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis.
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.
authors.affiliation: Department of Biology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Pillai-Kastoori
authors.affiliation: Department of Biology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Biology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Wilson
authors.affiliation: Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Erin
authors.initials: E
authors.lastname: Strachan
authors.affiliation: Department of Neuroscience, Pediatric Neurology Unit, "Tor Vergata" University of Rome, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Lo-Castro
authors.affiliation: Laboratory of Medical Genetics, IRCCS Associazione Oasi Maria Santissima, Troina, Italy, and Medical Genetics, University of Catania, Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.affiliation: Unit of Neurology, IRCCS Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: Sebastiano A
authors.initials: SA
authors.lastname: Musumeci
authors.affiliation: Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
authors.affiliation: Department of Biology, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Morris
mesh_terms: D000818:Animals; D015862:Choroid Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003103:Coloboma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics*; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D053823:Hedgehog Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D009024:Morphogenesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D055751:SOXC Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; D012333:RNA, Messenger; D055751:SOXC Transcription Factors; C524053:Shha protein, zebrafish; D029961:Zebrafish Proteins; C490794:sox11a protein, zebrafish