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Sox2 is required for sensory organ development in the mammalian inner ear

Nature volume 434, pages 1031–1035 (2005)Cite this article

Abstract

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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Figure 1: Inner ear malformations and sensory defects in Ysb and Lcc mice.
Figure 2: Altered expression of the Sox2 gene and protein in Ysb and Lcc mice and loss of inner ear prosensory domains.
Figure 3: Altered or loss of expression of SOX2 protein correlates with abnormal/loss of hair and supporting cell differentiation in Ysb/Ysb and Lcc/Lcc mice, respectively.
Figure 4: Sox2 functions upstream of Math1 during sensory organ formation.

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References

  1. Fekete, D. M., Muthukumar, S. & Karagogeos, D. Hair cells and supporting cells share a common progenitor in the avian inner ear. J. Neurosci. 18, 7811–7821 (1998)

    Article  CAS  Google Scholar 

  2. Dong, S. et al. Circling, deafness, and yellow coat displayed by yellow submarine (Ysb) and light coat and circling (Lcc) mice with mutations on chromosome 3. Genomics 79, 777–784 (2002)

    Article  CAS  Google Scholar 

  3. Eddison, M., Le, R. I. & Lewis, J. Notch signaling in the development of the inner ear: lessons from Drosophila. Proc. Natl Acad. Sci. USA 97, 11692–11699 (2000)

    Article  ADS  CAS  Google Scholar 

  4. Jan, Y. N. & Jan, L. Y. Neuronal cell fate specification in Drosophila. Curr. Opin. Neurobiol. 4, 8–13 (1994)

    Article  CAS  Google Scholar 

  5. Bermingham, N. A. et al. Math1: an essential gene for the generation of inner ear hair cells. Science 284, 1837–1841 (1999)

    Article  CAS  Google Scholar 

  6. Chen, P., Johnson, J. E., Zoghbi, H. Y. & Segil, N. The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination. Development 129, 2495–2505 (2002)

    Article  CAS  Google Scholar 

  7. Lyon, M. F., Phillips, R. J. & Fisher, G. Dose-response curves for radiation-induced gene mutations in mouse oocytes and their interpretation. Mutat. Res. 63, 161–173 (1979)

    Article  CAS  Google Scholar 

  8. Wood, H. B. & Episkopou, V. Comparative expression of the mouse Sox1, Sox2 and Sox3 genes from pre-gastrulation to early somite stages. Mech. Dev. 86, 197–201 (1999)

    Article  CAS  Google Scholar 

  9. Uchikawa, M., Kamachi, Y. & Kondoh, H. Two distinct subgroups of Group B Sox genes for transcriptional activators and repressors: their expression during embryonic organogenesis of the chicken. Mech. Dev. 84, 103–120 (1999)

    Article  CAS  Google Scholar 

  10. Avilion, A. A. et al. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 17, 126–140 (2003)

    Article  CAS  Google Scholar 

  11. Knowlton, V. Y. Correlation of the development of membranous and bony labyrinths, acoustics ganglia, nerves, and brain centers of the chick embryos. J. Morphol. 121, 179–208 (1967)

    Article  Google Scholar 

  12. Cole, L. K. et al. Sensory organ generation in the chicken inner ear: contributions of bone morphogenetic protein 4, serrate1, and lunatic fringe. J. Comp. Neurol. 424, 509–520 (2000)

    Article  CAS  Google Scholar 

  13. Zappone, M. V. et al. Sox2 regulatory sequences direct expression of a (beta)-geo transgene to telencephalic neural stem cells and precursors of the mouse embryo, revealing regionalization of gene expression in CNS stem cells. Development 127, 2367–2382 (2000)

    CAS  PubMed  Google Scholar 

  14. Uchikawa, M., Ishida, Y., Takemoto, T., Kamachi, Y. & Kondoh, H. Functional analysis of chicken Sox2 enhancers highlights an array of diverse regulatory elements that are conserved in mammals. Dev. Cell 4, 509–519 (2003)

    Article  CAS  Google Scholar 

  15. Cheah, K. S. et al. Human COL2A1-directed SV40 T antigen expression in transgenic and chimeric mice results in abnormal skeletal development. J. Cell Biol. 128, 223–237 (1995)

    Article  CAS  Google Scholar 

  16. Cai, J. et al. Properties of a fetal multipotent neural stem cell (NEP cell). Dev. Biol. 251, 221–240 (2002)

    Article  CAS  Google Scholar 

  17. Buescher, M., Hing, F. S. & Chia, W. Formation of neuroblasts in the embryonic central nervous system of Drosophila melanogaster is controlled by SoxNeuro. Development 129, 4193–4203 (2002)

    CAS  PubMed  Google Scholar 

  18. Overton, P. M., Meadows, L. A., Urban, J. & Russell, S. Evidence for differential and redundant function of the Sox genes Dichaete and SoxN during CNS development in Drosophila. Development 129, 4219–4228 (2002)

    CAS  PubMed  Google Scholar 

  19. Kishi, M. et al. Requirement of Sox2-mediated signaling for differentiation of early Xenopus neuroectoderm. Development 127, 791–800 (2000)

    CAS  PubMed  Google Scholar 

  20. Chen, P. & Segil, N. p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti. Development 126, 1581–1590 (1999)

    CAS  PubMed  Google Scholar 

  21. Zheng, J. L. & Gao, W. Q. Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nature Neurosci. 3, 580–586 (2000)

    Article  CAS  Google Scholar 

  22. Woods, C., Montcouquiol, M. & Kelley, M. W. Math1 regulates development of the sensory epithelium in the mammalian cochlea. Nature Neurosci. 7, 1310–1318 (2004)

    Article  CAS  Google Scholar 

  23. Chang, W., Brigande, J. V., Fekete, D. M. & Wu, D. K. The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. Development 131, 4201–4211 (2004)

    Article  CAS  Google Scholar 

  24. Pirvola, U. et al. FGFR1 is required for the development of the auditory sensory epithelium. Neuron 35, 671–680 (2002)

    Article  CAS  Google Scholar 

  25. Pauley, S. et al. Expression and function of FGF10 in mammalian inner ear development. Dev. Dyn. 227, 203–215 (2003)

    Article  CAS  Google Scholar 

  26. Kiernan, A. E. et al. The Notch ligand Jagged1 is required for inner ear sensory development. Proc. Natl Acad. Sci. USA 98, 3873–3878 (2001)

    Article  ADS  CAS  Google Scholar 

  27. Tsai, H. et al. The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum. Mol. Genet. 10, 507–512 (2001)

    Article  CAS  Google Scholar 

  28. Morsli, H., Choo, D., Ryan, A., Johnson, R. & Wu, D. K. Development of the mouse inner ear and origin of its sensory organs. J. Neurosci. 18, 3327–3335 (1998)

    Article  CAS  Google Scholar 

  29. Li, H., Liu, H. & Heller, S. Pluripotent stem cells from the adult mouse inner ear. Nature Med. 9, 1293–1299 (2003)

    Article  CAS  Google Scholar 

  30. Li, H., Roblin, G., Liu, H. & Heller, S. Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc. Natl Acad. Sci. USA 100, 13495–13500 (2003)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Amy E. Kiernan

    Present address: The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, USA

  2. Karen P. Steel

    Present address: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK

  3. Charles Tease

    Present address: Science Style, Courtland Road, Oxford, OX4 4JB, UK

  4. Amy E. Kiernan and Anna L. Pelling: These authors contributed equally to this work

Authors and Affiliations

  1. MRC Institute of Hearing Research, University of Nottingham, Nottingham, NG7 2RD, UK

    Amy E. Kiernan & Karen P. Steel

  2. Department of Biochemistry, The University of Hong Kong, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China

    Anna L. Pelling, Keith K. H. Leung, Anna S. P. Tang & Kathryn S. E. Cheah

  3. Division of Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Donald M. Bell & Robin Lovell-Badge

  4. MRC Mammalian Genetics Unit, Harwell, Didcot, OX11 ORD, UK

    Charles Tease

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Supplementary information

Supplementary Figure S1

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)

Supplementary Figure S2

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)

Supplementary Figure S3

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)

Supplementary Figure S4

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)

Supplementary Table S1

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)

Supplementary Figure Legends

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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