Abstract
Cyclin-dependent kinase 5 (CDK5) is abundantly expressed in post-mitotic cells including neurons. It is involved in multiple cellular events, such as cytoskeletal dynamics, signaling cascades, gene expression, and cell survival, et al. Dysfunction of CDK5 has been associated with a number of neurological disorders. Here we show that CDK5 is expressed in mouse cochlear hair cells, and CDK5 inactivation in hair cells causes hearing loss in mice. CDK5 inactivation has no effect on stereocilia development in the cochlear hair cells. However, it affects stereocilia maintenance, resulting in stereocilia disorganization and eventually stereocilia loss. Consistently, hair cell loss was significantly elevated by CDK5 inactivation. Despite that CDK5 has been shown to play important roles in synapse development and/or function, CDK5 inactivation does not affect the formation of ribbon synapses of cochlear hair cells. Further investigation showed that CDK5 inactivation causes reduced phosphorylation of ERM (ezrin, radixin, and moesin) proteins, which might contribute to the stereocilia deficits. Taken together, our data suggest that CDK5 plays pivotal roles in auditory hair cells, and CDK5 inactivation causes hearing loss in mice.
Highlights
In the mammalian cochlea, hair cells are arranged into one row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs) that are interlaced with various types of supporting cells (Schwander et al, 2010)
Cryosection immunostaining confirmed that Cyclin-dependent kinase 5 (CDK5) was present in the cell body of both IHCs and OHCs, and the immunoreactivity was more concentrated at the apical surface of hair cells (Supplementary Figure S1A)
It was shown that CDK5 and its activator p35 are highly expressed in primary afferent nociceptive fibers in mouse dorsal root ganglia, where they modulate nociceptive signaling through phosphorylation of transient receptor potential vanilloid 1 (TRPV1) (Pareek et al, 2006, 2007; Yang et al, 2007)
Summary
Hair cells are arranged into one row of inner hair cells (IHCs) and three rows of outer hair cells (OHCs) that are interlaced with various types of supporting cells (Schwander et al, 2010). Dozens to hundreds of stereocilia are organized into several rows of increasing heights, forming a staircase-like pattern. The vertices of stereocilia in all hair cells point away from the center of the cochlea, establishing the planar cell polarity (PCP) of the cochlear epithelia. A single microtubule-based kinocilium localizes at the vertex of stereocilia, but degenerates at late developmental stage in cochlear hair cells, implying that it is not necessary for MET (Lindeman et al, 1971). Kinocilium was believed to play pivotal roles in stereocilia development and cochlear PCP establishment (Jones et al, 2008). The detailed mechanisms of hair bundle development and maintenance as well as hair cell PCP establishment still remain elusive
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