Connexin30 mediated intercellular communication plays an essential role in epithelial repair in the cochlea

Abstract

SummaryA role for connexin (Cx)30 in epithelial repair following injury was examined in the organ of Corti, the sensory epithelium of the cochlea. In this tissue, lesions caused by loss of the sensory hair cells are closed by the supporting cells that surround each one. Gap junctions in which Cx30 is the predominant connexin are large and numerous between supporting cells. In mice carrying a deletion in the gene (Gjb6) that encodes Cx30, the size and number of gap junction plaques, and the extent of dye transfer, between supporting cells was greatly reduced compared with normal animals. This corresponded with unique peculiarities of the lesion closure events during the progressive hair cell loss that occurs in these animals in comparison with other models of hair cell loss, whether acquired or as a result of a mutation. Only one, rather than all, of the supporting cells that contacted an individual dying hair closed the lesion, indicating disturbance of the co-ordination of cellular responses. The cell shape changes that the supporting cells normally undergo during repair of the organ of Corti did not occur. Also, there was disruption of the migratory activities that normally lead to the replacement of a columnar epithelium with a squamous-like one. These observations demonstrate a role for Cx30 and intercellular communication in regulating repair responses in an epithelial tissue.

How to Bury the Dead: Elimination of Apoptotic Hair Cells from the Hearing Organ of the Mouse

“…Swelling has been previously reported following ototoxic and noise traumas (Fredelius 1988;Flock et al 1999;Ahmad et al 2003;Abrashkin et al 2006;Taylor et al 2012;Forge et al 2013). A possible trigger for this event is altered ion transport coupled with intercellular signaling between dying hair cells and supporting cells (Piazza et al 2007;Forge et al 2013). Thus, phalangeal swelling of DCs can serve as a protective ion buffering mechanism in the lesioned organ of Corti.…”

Cx30 exhibits unique characteristics including a long half-life when assembled into gap junctions

“…For example, in wounded skin, up-regulation of Cx30 and Cx26 in all epidermal keratinocyte layers, and a concomitant decrease in Cx43 at the wound edge, are proposed to co-ordinate the keratinocyte wound healing response (Coutinho et al, 2003;Churko and Laird, 2013). In the damaged cochlea, Cx30 is also important for coordinating a wound healing response after sensory hair cell death (Forge et al, 2013). In this instance, supporting cells expand to fill the voids left by dead hair cells and restore epithelial tight junction integrity.…”

“…In this instance, supporting cells expand to fill the voids left by dead hair cells and restore epithelial tight junction integrity. In Cx30 −/− mice, supporting cells not only display defects in repairing the space left by dead hair cells, they also develop a highly unusual migratory phenotype, despite still expressing Cx26, suggesting that Cx30 plaques may be important in controlling cell responses to injury (Forge et al, 2013). The inability of terminally differentiated keratinocytes and cochlear supporting cells to proliferate suggests that long-lived Cx30 gap junctions may help to regulate GJIC or cell-cell adhesion properties to collectively coordinate and control wound healing responses.…”

Grhl1 deficiency affects inner ear development in zebrafish

“…A typical barrier complex includes tight junctions, adherens junctions, and desmosomes. Previous studies have suggested that different types of intercellular junctions are important to normal ear function (Forge et al, 2013, Hardison et al, 2005, Zhu et al, 2013. Desmosome function in the organ of Corti is a largely unexplored area.…”

“…It is critical to various types of system development (Cenci and Gould, 2005, Gao et al, 2013, Han et al, 2011, Janicke et al, 2010, Sanchez-Calderon et al, 2007. For example, the GRH family is important to epithelial barrier development and post-wounding barrier repair via regulation of junction protein expression and to epithelial adhesion, which is essential to organ development (Hama) (Forge et al, 2013, Zhu et al, 2013. Within this family, GRHL2 has been confirmed to be related to DFNA28.…”