Compartmentalization established by claudin-11-based tight junctions in stria vascularis is required for hearing through generation of endocochlear potential

Abstract

Claudins are cell adhesion molecules working at tight junctions (TJs) that are directly involved in compartmentalization in multicellular organisms. The cochlea includes a rather peculiar compartment filled with endolymph. This compartment is characterized by high K+ concentration (∼150 mM) and a positive endocochlear potential (∼90 mV; EP), both indispensable conditions for cochlear hair cells to transduce acoustic stimuli to electrical signals. These conditions are thought to be generated by the stria vascularis, which is adjacent to the endolymph compartment. The stria vascularis itself constitutes an isolated compartment delineated by two epithelial barriers, marginal and basal cell layers. Because TJs of basal cells are primarily composed of claudin-11, claudin-11-deficient (Cld11-/-) mice were generated with an expectation that the compartmentalization in stria vascularis in these mice would be affected. Auditory brainstem response measurements revealed that Cld11-/- mice suffered from deafness; although no obvious gross morphological malformations were detected in Cld11-/- cochlea, freeze-fracture replica electron microscopy showed that TJs disappeared from basal cells of the stria vascularis. In good agreement with this, tracer experiments showed that the basal cell barrier was destroyed without affecting the marginal cell barrier. Importantly, in the endolymph compartment of Cld11-/- cochlea, the K+ concentration was maintained around the normal level (∼150 mM), whereas the EP was suppressed down to ∼30 mV. These findings indicated that the establishment of the stria vascularis compartment, especially the basal cell barrier, is indispensable for hearing ability through the generation/maintenance of EP but not of a high K+ concentration in the endolymph.

Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes

“…6H). The absence of expression of the basal cellspecific protein claudin 11 (Cldn11) (Gow et al, 2004;Kitajiri et al, 2004) in Tbx18KO mice (Fig. 6J) confirmed the dramatic reduction of the basal cell layer.…”

Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families

“…In the inner-ear epithelia, tricellulin is concentrated in tTJs (Riazuddin et al 2006), where the fluid-filled compartments of different ionic compositions of the organ of Corti are required for normal hearing (Kitajiri et al 2004). Riazuddin et al (2006) demonstrated the presence of at least four alternatively spliced TRIC isoforms (TRIC-a, TRIC-a1, TRIC-b, TRIC-c) in various mouse tissues.…”

Tight junction-based epithelial microenvironment and cell proliferation

“…Knockout mice for claudin-1 and -5 exhibit severe newborn lethal phenotypes because of defective water loss from their skin and defects in their blood-brain barrier, respectively (Morita et al, 1999a;Furuse et al, 2002;Nitta et al, 2003). Knockout mice for claudin-11 and -14 were associated with deafness arising from paracellular barrier-based permselective defects in the inner lymph system (Ben-Yosef et al, 2003; Kitajiri et al, 2004;Wattenhofer et al, 2005). It is noteworthy that deficiency of claudin-11 and -19 lead to defects in TJ formation and defective electrical sealing of glial myelin sheath cells in the central and peripheral nervous systems, respectively (Gow et al, 1999;Morita et al, 1999b;Miyamoto et al, 2005).…”