The lhfpl5 Ohnologs lhfpl5a and lhfpl5b Are Required for Mechanotransduction in Distinct Populations of Sensory Hair Cells in Zebrafish
Date
2020-01-15
Authors
Erickson, Timothy
Pacentine, Itallia V
Venuto, Alexandra
Clemens, Rachel
Nicolson, Teresa
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Abstract
Hair cells sense and transmit auditory, vestibular, and hydrodynamic information by
converting mechanical stimuli into electrical signals. This process of mechano-electrical
transduction (MET) requires a mechanically gated channel localized in the apical
stereocilia of hair cells. In mice, lipoma HMGIC fusion partner-like 5 (LHFPL5) acts
as an auxiliary subunit of the MET channel whose primary role is to correctly localize
PCDH15 and TMC1 to the mechanotransduction complex. Zebrafish have two lhfpl5
genes (lhfpl5a and lhfpl5b), but their individual contributions to MET channel assembly
and function have not been analyzed. Here we show that the zebrafish lhfpl5 genes
are expressed in discrete populations of hair cells: lhfpl5a expression is restricted to
auditory and vestibular hair cells in the inner ear, while lhfpl5b expression is specific
to hair cells of the lateral line organ. Consequently, lhfpl5a mutants exhibit defects in
auditory and vestibular function, while disruption of lhfpl5b affects hair cells only in the
lateral line neuromasts. In contrast to previous reports in mice, localization of Tmc1
does not depend upon Lhfpl5 function in either the inner ear or lateral line organ. In
both lhfpl5a and lhfpl5b mutants, GFP-tagged Tmc1 and Tmc2b proteins still localize
to the stereocilia of hair cells. Using a stably integrated GFP-Lhfpl5a transgene, we
show that the tip link cadherins Pcdh15a and Cdh23, along with the Myo7aa motor
protein, are required for correct Lhfpl5a localization at the tips of stereocilia. Our work
corroborates the evolutionarily conserved co-dependence between Lhfpl5 and Pcdh15,
but also reveals novel requirements for Cdh23 and Myo7aa to correctly localize Lhfpl5a.
In addition, our data suggest that targeting of Tmc1 and Tmc2b proteins to stereocilia
in zebrafish hair cells occurs independently of Lhfpl5 proteins.