Abstract
The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement. Stereocilia are interconnected by a variety of links and also carry an electron-dense surface coat. The coat may contribute to stereocilia adhesion or protect from stereocilia fusion, but its molecular identity remains unknown. From a database of hair-cell-enriched translated proteins, we identify Polycystic Kidney and Hepatic Disease 1-Like 1 (PKHD1L1), a large, mostly extracellular protein of 4249 amino acids with a single transmembrane domain. Using serial immunogold scanning electron microscopy, we show that PKHD1L1 is expressed at the tips of stereocilia, especially in the high-frequency regions of the cochlea. PKHD1L1-deficient mice lack the surface coat at the upper but not lower regions of stereocilia, and they develop progressive hearing loss. We conclude that PKHD1L1 is a component of the surface coat and is required for normal hearing in mice.
Highlights
The bundle of stereocilia on inner ear hair cells responds to subnanometer deflections produced by sound or head movement
Mammalian hair cells are post-mitotic, terminally differentiated sensory cells of the inner ear. They carry a bundle of actin-based stereocilia on their apical surfaces, which is deflected on a nanometer scale by either sound or head movements
We present results showing that Polycystic Kidney and Hepatic Disease 1Like 1 (PKHD1L1) localizes to stereocilia bundles, and participates in forming of the stereocilia surface coat, causing hearing loss when absent from the hair cells
Summary
PKHD1L1 (Fig. 2a) was identified as having these characteristics as well as being highly enriched in hair cells. The database showed much higher levels of translated Pkhd1l1 mRNA in hair cells at postnatal ages P0, P2, and P4, compared with translated Pkhd1l1 mRNA in spiral ganglion cells or the total Pkhd1l1 mRNA of the homogenized inner ear (Fig. 2b). Our previous database of all mRNAs isolated from hair cells[29] showed much higher transcription of Pkhd1l1 in hair cells compared to surrounding cells (Fig. 2c). PKHD1L1 is a large, 4249-aa protein (Fig. 2a) with a strongly predicted signal sequence, which is likely to be largely extracellular. It has a single transmembrane domain, and a very small, 8-aa intracellular C-terminus. PKHD1L1 has two G8 domains; these have 10 beta strands and an alpha helix, and are similar to, but larger than, the IPT domains[32]
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