Notch signalling is one of the most important cell-to-cell communication pathways during inner ear development and regeneration. We are developing and using live-imaging and genetic tricks in chicken embryos to understand the functions of Notch in i) establishing the early/prosensory domains of the inner ear and ii) the regulation of hair cell versus supporting cell fate decisions.
Collaborators: J. Gale (Ear Institute), J. Stone (U. Seattle, USA), K. Steel (Wellcome Trust Sanger Institute), B. Alsina (U. Pompeu Fabra, Spain)
Chrysostomou E, Gale J, Daudet N. Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: evidence against cis-inhibition. Development (2012) vol. 139 (20) pp. 3764-3774
Bird J, Daudet N, Warchol M, Gale J. Supporting cells eliminate dying sensory hair cells to maintain epithelial integrity in the avian inner ear. J Neurosci (2010) vol. 30 (37) pp. 12545-56
Daudet N, Gibson R, Shang J, Bernard A, Lewis J, Stone J. Notch regulation of progenitor cell behavior in quiescent and regenerating auditory epithelium of mature birds. Dev Biol (2009) vol. 326 (1) pp. 86-100
Daudet N, Ariza-McNaughton L, Lewis J. Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear. Development (2007) vol. 134 (12) pp. 2369-78
We are using transcriptome analysis and functional approaches in vivo and in vitro to get new insights into the genetic networks regulated by Notch signalling during ear development. We are also interested in the specific roles of the SoxB family transcription factors in the control of hair cell formation and regeneration.
Freeman and Daudet. Artificial induction of Sox21 regulates sensory cell differentiation in the chick inner ear. Plos One (2012) in press
Stereocilia are microvilli-like structures arranged into a neat bundle at the surface of each hair cell. When fluid movements occur in the liquid-filled compartments of the inner ear, stereocilia are displaced, triggering the release of neurotransmitters by hair cells. Mutations in genes encoding molecular components of stereocilia are frequently associated to hereditary forms of deafness. In this collaborative and multidisciplinary project, we are investigating the specific role of an actin-bundling protein named Plastin1 (also known as Fimbrin), in stereocilia formation and auditory function in mouse.
Collaborators: A. Bullen, A. Forge, R. Taylor (Ear Institute), Francisco Rivero (U. of Hull), Stuart Johnson, Walter Marcotti (U. of Sheffield)
Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice
Hearing relies on the mechanosensory inner and outer hair cells (OHCs) of the organ of Corti, which convert mechanical deflections of their actin-rich stereociliary bundles into electrochemical signals. Several actin-associated proteins are essential for stereocilia formation and maintenance, and their absence leads to deafness. One of the most abundant actin-bundling proteins of stereocilia is plastin 1, but its function has never been directly assessed. Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies. Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length. The stereocilia of OHCs were comparatively less affected; however, they also showed signs of degeneration in ageing mice. The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents. These results show that in contrast to other actin-bundling proteins such as espin, harmonin or Eps8, plastin 1 is dispensable for the initial formation of stereocilia. However, the progressive hearing loss and morphological defects of hair cells in adult Pls1 KO mice point at a specific role for plastin 1 in the preservation of adult stereocilia and optimal hearing. Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss.
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