Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.

Seham Ebrahim,Morag A Lewis,Michael J.C Rogers,Bechara Kachar,Karen P Steel,Johanna C Pass,Neil J Ingham,Runjia Cui

doi:10.1016/j.celrep.2016.03.081

Seham Ebrahim, Morag A Lewis + Show 6 more

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https://doi.org/10.1016/j.celrep.2016.03.081

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SummaryWHRN (DFNB31) mutations cause diverse hearing disorders: profound deafness (DFNB31) or variable hearing loss in Usher syndrome type II. The known role of WHRN in stereocilia elongation does not explain these different pathophysiologies. Using spontaneous and targeted Whrn mutants, we show that the major long (WHRN-L) and short (WHRN-S) isoforms of WHRN have distinct localizations within stereocilia and also across hair cell types. Lack of both isoforms causes abnormally short stereocilia and profound deafness and vestibular dysfunction. WHRN-S expression, however, is sufficient to maintain stereocilia bundle morphology and function in a subset of hair cells, resulting in some auditory response and no overt vestibular dysfunction. WHRN-S interacts with EPS8, and both are required at stereocilia tips for normal length regulation. WHRN-L localizes midway along the shorter stereocilia, at the level of inter-stereociliary links. We propose that differential isoform expression underlies the variable auditory and vestibular phenotypes associated with WHRN mutations.

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Inner ear sensory hair cells (HCs) transduce sound and head motion to electrical impulses via their mechanosensory hair bundles
We show that normal stereocilia are maintained in cochlear inner hair cells (IHCs) of the Whrntm1b mutant, but outer hair cell (OHC) stereocilia morphology, organization, and function are affected
We show that WHRN-S localizes to the tips of stereocilia of IHCs from birth to adulthood, colocalizes with the actin regulatory protein EPS8, and is required for normal stereocilia length regulation

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Inner ear sensory hair cells (HCs) transduce sound and head motion to electrical impulses via their mechanosensory hair bundles. Each hair bundle comprises dozens of specialized actinfilled protrusions, called stereocilia, organized in rows of graded heights. Stereocilia heights and organization have important effects on the HC’s operating range, sensitivity, and frequency selectivity (Aranyosi and Freeman, 2004), and a number of proteins involved in regulating stereocilia morphology are essential for normal hearing (Dror and Avraham, 2009). The PDZ domain-containing protein whirlin (WHRN) has been shown to localize to the tips of stereocilia, where it is involved in length-regulation (Delprat et al, 2005; Holme et al, 2002; Manor et al, 2011), and to the stereocilia base, where it is thought to play a role in the bundle organization during development (Delprat et al, 2005).

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