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Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression.

Kim HM, Wangemann P - PLoS ONE (2010)

Bottom Line: Cochlear lumen formation was found to begin at the base of the cochlea between embryonic day (E) 13.5 and 14.5.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.

View Article: PubMed Central - PubMed

Affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas, United States of America.

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.

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Diagram of ion transport in the endolymphatic sac.The endolymphatic sac epithelium consists mainly of ribosomal-rich cells that are interspersed by mitochondrial-rich cells. Mitochondrial-rich cells express H+ ATPase and the Cl−/HCO3− exchanger pendrin in their apical membrane. Ribosomal-rich cells express Na+ channels including ENaC. A current generated by the H+ ATPase drives Na+ reabsorption via Na+ channels. The role of the Cl−/HCO3− exchanger pendrin is to export HCO3− that is generated by carbonic anhydrase (CA) in the reaction that leads to the generation of H+.
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pone-0014041-g010: Diagram of ion transport in the endolymphatic sac.The endolymphatic sac epithelium consists mainly of ribosomal-rich cells that are interspersed by mitochondrial-rich cells. Mitochondrial-rich cells express H+ ATPase and the Cl−/HCO3− exchanger pendrin in their apical membrane. Ribosomal-rich cells express Na+ channels including ENaC. A current generated by the H+ ATPase drives Na+ reabsorption via Na+ channels. The role of the Cl−/HCO3− exchanger pendrin is to export HCO3− that is generated by carbonic anhydrase (CA) in the reaction that leads to the generation of H+.

Mentions: The concept that the endolymphatic sac is engaged in fluid absorption is not new although a direct, in vitro, demonstration of fluid absorption is so far lacking. Indirect evidence for an absorptive function comes from the observation that anoxia leads to a rise in the luminal Na+ and Cl− concentrations [25], [26] and that obliteration of the endolymphatic sac in adult guinea pigs to an enlargement of the cochlear lumen [27]. Investigations of the endolymphatic sac are hampered by the difficulty of access and the heterogeneity of the epithelium, which consists principally of ribosome-rich cells with interspersed mitochondrial-rich cells [28]. Nevertheless, a number of ion transporters have been identified. These include apical Na+ channels [29], [30], apical H+ ATPase subunits [23], [31], [32], basolateral Na+/K+ ATPases [33], basolateral Na+/H+ exchangers [34], [35] and apical as well as basolateral Cl−/HCO3− exchangers including pendrin [11], [23], [31]. The epithelium generates a lumen-positive transepithelial potential that is sensitive to inhibition of Na+ channels, H+ ATPase, Cl−/HCO3− exchangers, Na+/H+ exchangers and carbonic anhydrase [25], [36]. It is intriguing to speculate that the heterogenic epithelium of the endolymphatic sac resembles a frog skin in that it engages in H+ ATPase-driven Na+ reabsorption. Frog skin is comprised of principal cells equipped with apical Na+ channels and mitochondria-rich cells equipped with an apical H+ ATPase and a Cl−/HCO3− exchanger. Highly effective Na+ absorption is powered by the H+ ATPase, which generates a current that drives Na+ absorption through the Na+ channels [37]. The role of the Cl−/HCO3− exchangers is this model is to export HCO3− that is generated by carbonic anhydrase in the process of generating H+ as substrate for the H+ ATPase (Fig. 10). Lack of the Cl−/HCO3− exchanger pendrin would inhibit H+ production by carbonic anhydrase through product-inhibition and a reduce the current that drives Na+ reabsorption.


Failure of fluid absorption in the endolymphatic sac initiates cochlear enlargement that leads to deafness in mice lacking pendrin expression.

Kim HM, Wangemann P - PLoS ONE (2010)

Diagram of ion transport in the endolymphatic sac.The endolymphatic sac epithelium consists mainly of ribosomal-rich cells that are interspersed by mitochondrial-rich cells. Mitochondrial-rich cells express H+ ATPase and the Cl−/HCO3− exchanger pendrin in their apical membrane. Ribosomal-rich cells express Na+ channels including ENaC. A current generated by the H+ ATPase drives Na+ reabsorption via Na+ channels. The role of the Cl−/HCO3− exchanger pendrin is to export HCO3− that is generated by carbonic anhydrase (CA) in the reaction that leads to the generation of H+.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2984494&req=5

pone-0014041-g010: Diagram of ion transport in the endolymphatic sac.The endolymphatic sac epithelium consists mainly of ribosomal-rich cells that are interspersed by mitochondrial-rich cells. Mitochondrial-rich cells express H+ ATPase and the Cl−/HCO3− exchanger pendrin in their apical membrane. Ribosomal-rich cells express Na+ channels including ENaC. A current generated by the H+ ATPase drives Na+ reabsorption via Na+ channels. The role of the Cl−/HCO3− exchanger pendrin is to export HCO3− that is generated by carbonic anhydrase (CA) in the reaction that leads to the generation of H+.
Mentions: The concept that the endolymphatic sac is engaged in fluid absorption is not new although a direct, in vitro, demonstration of fluid absorption is so far lacking. Indirect evidence for an absorptive function comes from the observation that anoxia leads to a rise in the luminal Na+ and Cl− concentrations [25], [26] and that obliteration of the endolymphatic sac in adult guinea pigs to an enlargement of the cochlear lumen [27]. Investigations of the endolymphatic sac are hampered by the difficulty of access and the heterogeneity of the epithelium, which consists principally of ribosome-rich cells with interspersed mitochondrial-rich cells [28]. Nevertheless, a number of ion transporters have been identified. These include apical Na+ channels [29], [30], apical H+ ATPase subunits [23], [31], [32], basolateral Na+/K+ ATPases [33], basolateral Na+/H+ exchangers [34], [35] and apical as well as basolateral Cl−/HCO3− exchangers including pendrin [11], [23], [31]. The epithelium generates a lumen-positive transepithelial potential that is sensitive to inhibition of Na+ channels, H+ ATPase, Cl−/HCO3− exchangers, Na+/H+ exchangers and carbonic anhydrase [25], [36]. It is intriguing to speculate that the heterogenic epithelium of the endolymphatic sac resembles a frog skin in that it engages in H+ ATPase-driven Na+ reabsorption. Frog skin is comprised of principal cells equipped with apical Na+ channels and mitochondria-rich cells equipped with an apical H+ ATPase and a Cl−/HCO3− exchanger. Highly effective Na+ absorption is powered by the H+ ATPase, which generates a current that drives Na+ absorption through the Na+ channels [37]. The role of the Cl−/HCO3− exchangers is this model is to export HCO3− that is generated by carbonic anhydrase in the process of generating H+ as substrate for the H+ ATPase (Fig. 10). Lack of the Cl−/HCO3− exchanger pendrin would inhibit H+ production by carbonic anhydrase through product-inhibition and a reduce the current that drives Na+ reabsorption.

Bottom Line: Cochlear lumen formation was found to begin at the base of the cochlea between embryonic day (E) 13.5 and 14.5.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.

View Article: PubMed Central - PubMed

Affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, Kansas, United States of America.

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.

Show MeSH
Related in: MedlinePlus