A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle

Kirsten Dutton, Leila Abbas, Joanne Spencer, Claire Brannon, Catriona Mowbray, Masataka Nikaido, Robert N. Kelsh, Tanya T. Whitfield

Research output: Contribution to journalArticle

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Abstract

In humans, mutations in the SOX10 gene area cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.
LanguageEnglish
Pages68-83
Number of pages16
JournalDisease Models & Mechanisms
Volume2
Issue number1-2
Early online date22 Dec 2008
DOIs
StatusPublished - Jan 2009

Fingerprint

Waardenburg Syndrome
Zebrafish
Ear
Genes
HMGB Proteins
Tissue
Gene expression
Fish
Labeling
Neural Crest
Derivatives
Defects
Cochlea
Deafness
Epithelium
Experiments
Stria Vascularis
Phenotype
Haploinsufficiency
Mutation

Keywords

  • transcription factor sox10
  • inner-ear development
  • marie-tooth-disease
  • neural crest cells
  • stria vascularis
  • enteric nervous-system
  • hirschsprung-disease
  • b receptor gene
  • chronic intestinal pseudoobstruction
  • embryonic zebrafish

Cite this

Dutton, K., Abbas, L., Spencer, J., Brannon, C., Mowbray, C., Nikaido, M., ... Whitfield, T. T. (2009). A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. DOI: 10.1242/dmm.001164

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. / Dutton, Kirsten; Abbas, Leila; Spencer, Joanne; Brannon, Claire; Mowbray, Catriona; Nikaido, Masataka; Kelsh, Robert N.; Whitfield, Tanya T.

In: Disease Models & Mechanisms, Vol. 2, No. 1-2, 01.2009, p. 68-83.

Research output: Contribution to journalArticle

Dutton, K, Abbas, L, Spencer, J, Brannon, C, Mowbray, C, Nikaido, M, Kelsh, RN & Whitfield, TT 2009, 'A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle' Disease Models & Mechanisms, vol. 2, no. 1-2, pp. 68-83. DOI: 10.1242/dmm.001164
Dutton K, Abbas L, Spencer J, Brannon C, Mowbray C, Nikaido M et al. A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. Disease Models & Mechanisms. 2009 Jan;2(1-2):68-83. Available from, DOI: 10.1242/dmm.001164
Dutton, Kirsten ; Abbas, Leila ; Spencer, Joanne ; Brannon, Claire ; Mowbray, Catriona ; Nikaido, Masataka ; Kelsh, Robert N. ; Whitfield, Tanya T./ A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle. In: Disease Models & Mechanisms. 2009 ; Vol. 2, No. 1-2. pp. 68-83
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abstract = "In humans, mutations in the SOX10 gene area cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.",
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