The Waardenburg syndromes are rare genetic disorders characterised by both deafness and pigmentation abnormalities. Classically, they are described as neural crest syndromes; the hearing loss in patients has been attributed to the loss of neural-crest-derived pigment cells in the cochlea of the inner ear, where these cells play an essential role in hearing. Waardenburg syndrome type IV (WS4) and other variants can be caused by dominant mutations in the SOX10 gene, which codes for a transcriptional regulator that is essential for pigment cell development. However, SOX10 is not only expressed in the neural crest, but also in the developing inner ear itself. This raises the possibility that the hearing loss and other inner ear defects seen in WS4 patients could result from the loss of a direct function of SOX10 in the ear, rather than an indirect loss of neural-crest-derived pigment cells.

We have used a zebrafish model of WS4, the colourless/sox10 mutant. This mutant displays the same spectrum of abnormalities as found in WS4 patients, affecting the ear, pigment cells and enteric neurons. By labelling neural crest cells, we have shown that a few neural crest cells do normally contribute to the zebrafish ear as it develops, but the loss of these cells is unlikely to account for the severe ear defects found in the mutant. Much more strikingly, the loss of sox10 function results in gene expression abnormalities in the developing ear from early stages, including the misregulation of genes coding for signalling molecules such as Fgf8 and Bmp4. As a result, severe structural and sensory abnormalities of the ear develop at later stages, including defects in the semicircular canals, sensory patches and endolymphatic duct. Thus, sox10 (together with the related sox9 genes) is crucial for establishing and maintaining correct patterns of gene expression in the inner ear at early stages of development.

This study demonstrates a direct role for Sox10 in the developing zebrafish ear, and raises the possibility that hearing loss in WS4 patients carrying SOX10 mutations could be compounded by structural and functional deficits in addition to the loss of neural-crest-derived pigment cells in the inner ear. Our findings are corroborated by descriptions of severe inner ear structural abnormalities in WS patients carrying SOX10 mutations, which would be very unlikely to result from the loss of pigment cells alone. This work helps us to understand the aetiology of the inner ear defects in these patients and to explain both hearing loss and any vestibular problems in cases of WS caused by SOX10 mutations.

2009