Sensory hair cells and their associated non-sensory supporting cells in the inner ear are fundamental for hearing and balance. They arise from a common progenitor1, but little is known about the molecular events specifying this cell lineage. We recently identified two allelic mouse mutants, light coat and circling (Lcc) and yellow submarine (Ysb), that show hearing and balance impairment2. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired2. We report here that inner ears of Lcc/Lcc mice fail to establish a prosensory domain and neither hair cells nor supporting cells differentiate, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice shows abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor SOX2, specifically within the developing inner ear. SOX2 continues to be expressed in the inner ears of mice lacking Math1 (also known as Atoh1 and HATH1), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1.
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This work was supported by grants from the Research Grants Council (Hong Kong) to K.S.E.C., by the UK Medical Research Council, Defeating Deafness, the European Commission and the Louis Jeantet Foundation. We thank C. L. So and M. Chan for mouse care and research assistance, and H. Zoghbi for the gift of Math1 null mice. We are also grateful to P. Tam, D. Loebel, V. Episkopou, J. Brigande and the RLB laboratory for critical comments and discussion.
The authors declare that they have no competing financial interests.
This figure shows the sensory defects in both the cochlea and vestibule of Ysb/Ysb inner ears at P0-P1 identified by scanning electron microscopy. (PDF 603 kb)
This figure shows that loss/downregulation of SOX2 expression correlates with absence/irregular hair cell differentiation in Lcc/Lcc and Ysb/Ysb vestibules, respectively as determined by immunohistochemistry at E16.5 using antibodies to SOX2 and MYO7A. (PDF 215 kb)
This figure shows that hair cell markers Pou4f3 and GFI1 are expressed in Ysb/Ysb cochlea hair cells at E16.5. The gene expression also shows the abnormal hair cell differentiation in Ysb/Ysb. (PDF 66 kb)
This figure shows the genomic DNA sequence that is amplified during the PCR genotyping of Lcc mutants. The naturally occurring polymorphism (SINE) in Lcc wild type DNA which does not segregate with the Lcc allele is highlighted as are the primer sequences. (PDF 167 kb)
This table shows the raw data from the endocochlear potential measurements of each mouse mutant. The results show that most mutants mutants have an endocochlear potential within the normal range. (DOC 24 kb)
Legends to accompany the above Supplementary Figures and Supplementary Table. (DOC 25 kb)
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Kiernan, A., Pelling, A., Leung, K. et al. Sox2 is required for sensory organ development in the mammalian inner ear. Nature 434, 1031–1035 (2005). https://doi.org/10.1038/nature03487
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