TitleFGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia.
Publication TypeJournal Article
Year of Publication2018
AuthorsHonda A, Kita T, Seshadri SVidhya, Misaki K, Ahmed Z, Ladbury JE, Richardson GP, Yonemura S, Ladher RK
JournalProc Natl Acad Sci U S A
Date Published2018 08 14
KeywordsAdaptor Proteins, Vesicular Transport, Animals, Cadherins, Chick Embryo, Clathrin, Flagella, Hair Cells, Auditory, Inner, Mice, Phosphorylation, Protein Precursors, Protein Transport, Receptor, Fibroblast Growth Factor, Type 1

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID30061390
PubMed Central IDPMC6099903