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

Abstract

SUMMARYIn humans, mutations in the SOX10 gene are a 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.

Spectrum of Temporal Bone Abnormalities in Patients with Waardenburg Syndrome andSOX10Mutations

“…Other differences have been observed across species: In Sox10 mutant zebrafish, the otic vesicle is smaller or distended, semicircular canals have a delayed development and are thinner than normal, and the sensory epithelia are incorrectly patterned. 35 These expression and functional studies, in combination with our findings, suggest that cochleosaccular degeneration is not the only mechanism leading to SNHL in patients carrying SOX10 mutations. It is tempting to correlate the high frequency of vestibular malformations to vestibular dysfunction.…”

“…The mean value of the CNC diameter for our patients was 1.66 Ϯ 0. 35 Because true agenesis of SCCs may be difficult to differentiate from a dysmorphic vestibule, an SCC was considered absent when no arch was visible, even if a small deformity of the vestibule, such as a small bud that could be an anlage, was present (Fig 3). The posterior SCCs were absent in 10 patients, had a thick arch of small diameter in 4, and were normal in 1 patient.…”

Zebrafish as a Model for Monocarboxyl Transporter 8-Deficiency

“…The location and shape of these cells was similar to SOX10-positive oligodendrocyte; the myelin-forming cells (36,37). These results suggest that MCT8 transports THs from the blood vessels into oligodendrocytes and neurons, and regulates myelination and neuron development.…”

“…In addition, mct8 expression was observed in oval cell bodies with short projections that did not express both HUC and GFAP markers. Because the structure and the location of these cells are similar to sox10 expressing cells (36,37), they are likely to be oligodendrocytes. Similarly, in mammals, mct8 mRNA and protein were present in oligodendroglial cells derived from mice (50).…”

Zebrafish: an animal model for research in veterinary medicine

“…Gene sox10 in the mutant, also known as colourless (cls), shows a strong conservation of gene expression pattern and function (Dutton et al 2009). This mutation responds both for depigmentation and agangliosis, mainly in the inner ear and enteric nervous system (Carney et al 2006).…”