Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

Lakshmi Pillai-Kastoori, Wen Wen, Stephen G. Wilson, Erin Strachan, Adriana Lo-Castro, Marco Fichera, Sebastiano A. Musumeci, Ordan J. Lehmann, Ann C. Morris

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Article numbere1004491
JournalPLoS Genetics
Volume10
Issue number7
DOIs
Publication statusPublished - 2014

Fingerprint

Hedgehogs
Erinaceidae
Coloboma
morphogenesis
Morphogenesis
Vertebrates
phenotype
vertebrate
eyes
vertebrates
Microphthalmos
Zebrafish
Danio rerio
fissure
Phenotype
Choroid
Lens
Lenses
Cyclopia
Anophthalmos

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)
  • Medicine(all)

Cite this

Pillai-Kastoori, L., Wen, W., Wilson, S. G., Strachan, E., Lo-Castro, A., Fichera, M., ... Morris, A. C. (2014). Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis. PLoS Genetics, 10(7), [e1004491]. https://doi.org/10.1371/journal.pgen.1004491

Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis. / Pillai-Kastoori, Lakshmi; Wen, Wen; Wilson, Stephen G.; Strachan, Erin; Lo-Castro, Adriana; Fichera, Marco; Musumeci, Sebastiano A.; Lehmann, Ordan J.; Morris, Ann C.

In: PLoS Genetics, Vol. 10, No. 7, e1004491, 2014.

Research output: Contribution to journalArticle

Pillai-Kastoori, L, Wen, W, Wilson, SG, Strachan, E, Lo-Castro, A, Fichera, M, Musumeci, SA, Lehmann, OJ & Morris, AC 2014, 'Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis', PLoS Genetics, vol. 10, no. 7, e1004491. https://doi.org/10.1371/journal.pgen.1004491
Pillai-Kastoori, Lakshmi ; Wen, Wen ; Wilson, Stephen G. ; Strachan, Erin ; Lo-Castro, Adriana ; Fichera, Marco ; Musumeci, Sebastiano A. ; Lehmann, Ordan J. ; Morris, Ann C. / Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis. In: PLoS Genetics. 2014 ; Vol. 10, No. 7.
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