Title:

Regulation of Protein Trafficking in the Hair Cell of the Inner Ear

 

Speaker:

Raj Ladher
National Centre for Biological Sciences, Bangalore, India

 

Abstract:
The generation of specialized cells, with specialized morphologies that carry out specialized functions, is one of the central problems in developmental biology. In the inner ear, mechanosensory hair cells (HCs) utilizes a distinctive apical architecture, the hair bundle, that deflects in response to sound or balance information. The hair bundle is made up of a specialized cilium, the kinocilium adjacent to the mechanosensory actin-based projections known as stereocilia (Peng, Salles, Pan, & Ricci, 2011). Mechanotransduction occurs in stereocilia and relies on filamentous connectors made of the transmembrane proteins, cadherin-23 (Cdh23) and protocadherin-15 (Pcdh15) (Petit & Richardson, 2009). These tip-links bridge the tip of the shortest stereocilia with the lateral wall of the next tallest neighbour. For both development and function, these proteins must be deployed to either kinocilia or stereocilia, however the mechanisms of targeting are not known. We have found that Pcdh15 deployment relies on cell-type specific hitching to the generic transport mechanism. We uncover a new role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles, specifically in hair cells. We find that upon activation, FGFR1 binds, phosphorylates and deploys protocadherin-15 (Pcdh15) to the kinocilia. Our results identify a kinociliary transport pathway, coordinated by FGFR1 activity and regulating hair bundle morphogenesis (Honda et al., 2018). We extend these studies to ask if a similar mechanism is functioning in the stereocilia and what role phosphorylation of Pcdh15 may play in the coordination of the mechanotransduction complex at stereociliary tips.

 

References:

Honda, A., Kita, T., Seshadri, S. V., Misaki, K., Ahmed, Z., Ladbury, J. E., et al. (2018). FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia. Proceedings of the National Academy of Sciences, 4, 201719861. http://doi.org/10.1073/pnas.1719861115
Peng, A. W., Salles, F. T., Pan, B., & Ricci, A. J. (2011). Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction. Nature Communications, 2(1), 523. http://doi.org/10.1038/ncomms1533
Petit, C., & Richardson, G. P. (2009). Linking genes underlying deafness to hair-bundle development and function. Nature Neuroscience, 12(6), 703–710. http://doi.org/10.1038/nn.2330