Abstract
Mutations of SLC26A4 are among the most prevalent causes of hereditary deafness. Deafness in the corresponding mouse model, Slc26a4−/−, results from an abnormally enlarged cochlear lumen. The goal of this study was to determine whether the cochlear enlargement originates with defective cochlear fluid transport or with a malfunction of fluid transport in the connected compartments, which are the vestibular labyrinth and the endolymphatic sac. Embryonic inner ears from Slc26a4+/− and Slc26a4−/− mice were examined by confocal microscopy ex vivo or after 2 days of organ culture. Culture allowed observations of intact, ligated or partially resected inner ears. Cochlear lumen formation was found to begin at the base of the cochlea between embryonic day (E) 13.5 and 14.5. Enlargement was immediately evident in Slc26a4−/− compared to Slc26a4+/− mice. In Slc26a4+/− and Slc26a4−/− mice, separation of the cochlea from the vestibular labyrinth by ligation at E14.5 resulted in a reduced cochlear lumen. Resection of the endolymphatic sacs at E14.5 led to an enlarged cochlear lumen in Slc26a4+/− mice but caused no further enlargement of the already enlarged cochlear lumen in Slc26a4−/− mice. Ligation or resection performed later, at E17.5, did not alter the cochlea lumen. In conclusion, the data suggest that cochlear lumen formation is initiated by fluid secretion in the vestibular labyrinth and temporarily controlled by fluid absorption in the endolymphatic sac. Failure of fluid absorption in the endolymphatic sac due to lack of Slc26a4 expression appears to initiate cochlear enlargement in mice, and possibly humans, lacking functional Slc26a4 expression.
Highlights
Mutations of SLC26A4 are worldwide among the most prevalent causes of deafness [1,2,3,4]
The most salient findings of this study are 1) that lumen formation begins between E13.5 and E14.5 at the base of the cochlea, 2) that the cochlea lumen is transiently, prior to E17.5, controlled by fluid secretion in the vestibular labyrinth and absorption in the endolymphatic sac and 3) that loss of pendrin expression leads to an enlargement of the cochlear lumen that is similar to the enlargement caused by resection of the endolymphatic sac
Pendrin is an anion exchanger that is prominently expressed in the cochlea, the vestibular labyrinth and the endolymphatic sac
Summary
Mutations of SLC26A4 are worldwide among the most prevalent causes of deafness [1,2,3,4]. The compatibility of SLC26A4 mutations with hearing, limited to early childhood, provides the imperative to investigate the etiology of SLC26A4 related deafness with the ultimate goal to develop strategies to preserve hearing in afflicted individuals. Toward this goal, the first mouse model, Slc26a42/2 (formerly named Pds2/2), had been developed [9]. The first mouse model, Slc26a42/2 (formerly named Pds2/2), had been developed [9] Studies using this mouse model have mainly focused on the postnatal development since normal mice acquire hearing during the second postnatal week and since most human patients lose hearing during early childhood.
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