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Notch signalling pathway mediates hair cell development in mammalian cochlea

Abstract

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster1,2. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct1. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells3,4,5 (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition6. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates7,8,9. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.

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Figure 1: Expression of Notch1 and Jag2 in the developing mouse cochlea at E14.5 and E18.
Figure 2: Light and electron microscopy of control versus Jag2 mutants.
Figure 3: Model of the role of the Notch pathway during the development of the organ of Corti.

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Acknowledgements

We thank M. Donohue for technical assistance; Y. Raz for initial work on this project; T. Maugel and the Laboratory for Biological Ultrastructure at the University of Maryland at College Park (contrib. 89) for use of the SEM; and D. Cotanche, M. Warchol, A. Popper, V. Papadopoulous and T. Reh for reviewing the manuscript. P.J.L. is supported by an NRSA from NIH/NIDCD, R.J. is supported by an NRSA from NIH/NICHD and Y.L. is supported by an institutional training grant awarded to the Jackson Laboratory by NIH. This research was supported by grants from the March of Dimes (T.G. and M.W.K.) as well as by the National Organization for Hearing Research and an Independent Scientist Award (K02) from NIDCD (M.W.K.).

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Correspondence to Matthew W. Kelley.

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Lanford, P., Lan, Y., Jiang, R. et al. Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 21, 289–292 (1999). https://doi.org/10.1038/6804

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