A conserved function of Pkhd1l1, a mammalian hair cell stereociliary coat protein, in regulating hearing in zebrafish

Abstract

Pkhd1l1 is predicted to encode a very large type-I transmembrane protein, but its function has largely remained obscure. Recently, it was shown that Pkhdl1l1 is a component of the coat that decorates stereocilia of outer hair cells in the mouse ear. Consistent with this localization, conditional deletion of Pkhd1l1 specifically from hair cells, was associated with progressive hearing loss. In the zebrafish, there are two paralogous pkhd1l1 genes - pkhd1l1α and pkhd1l1β. Using CRISPR-Cas9 mediated gene editing, we generated loss-of-function alleles for both and show that the double mutants exhibit nonsense-mediated-decay (NMD) of the RNAs. With behavioural assays, we demonstrate that zebrafish pkhd1l1 genes also regulate hearing; however, in contrast to Pkhd1l1 mutant mice, which develop progressive hearing loss, the double mutant zebrafish exhibited statistically significant hearing loss even from the larval stage. Our data highlight a conserved function of Pkhd1l1 in hearing and based on these findings from animal models, we postulate that PKHD1L1 could be a candidate gene for sensorineural hearing loss (SNHL) in humans.

Keywords:

• pkhd1l1
• zebrafish
• hair cell
• stereociliary coat
• sensorineural hearing loss

Acknowledgements

We thank V. Narasimhan for assistance with CRISPR-Cas9 genome editing.

Author contributions

S.M. and S.R. conceived the study; S.M. R-K.C. and H.L. performed the experiments and analysed the data; S.M. and S.R. wrote the manuscript that was read and endorsed by all other authors.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

S.M. was supported by the Singapore International Graduate Award (SINGA) and the experimental work was supported by funds from the Agency for Science, Technology and Research (A*STAR) of Singapore to S. R [grant no: SC15-R0010].