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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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Cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice.A, D and G: Luminal area measurements of cross-section #1 in cochleae obtained from E14.5, E16.5 and E18.5 littermates, respectively. The number next to the bars represents the N number of animals. Significant differences are marked (*). B and C, cochlear cross-sections of E14.5 Slc26a4+/− and Slc26a4−/− littermates. E and F, cochlear cross-sections of E16.5 Slc26a4+/− and Slc26a4−/− littermates. H and I, cochlear cross-sections of E18.5 Slc26a4+/− and Slc26a4−/− littermates. Scala media was highlighted in pink. Images without the pink overlay are available in Figure S1 (Supporting information). Arrows point to cross-section #1, which was used for digital area measurements. F-actin (green) was labeled. Cochlear cross-sections were imaged by laser-scanning microscopy.
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pone-0014041-g004: Cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice.A, D and G: Luminal area measurements of cross-section #1 in cochleae obtained from E14.5, E16.5 and E18.5 littermates, respectively. The number next to the bars represents the N number of animals. Significant differences are marked (*). B and C, cochlear cross-sections of E14.5 Slc26a4+/− and Slc26a4−/− littermates. E and F, cochlear cross-sections of E16.5 Slc26a4+/− and Slc26a4−/− littermates. H and I, cochlear cross-sections of E18.5 Slc26a4+/− and Slc26a4−/− littermates. Scala media was highlighted in pink. Images without the pink overlay are available in Figure S1 (Supporting information). Arrows point to cross-section #1, which was used for digital area measurements. F-actin (green) was labeled. Cochlear cross-sections were imaged by laser-scanning microscopy.

Mentions: In a second set of experiments, we compared the onset of cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice and monitored the progression of the enlargement between E14.5 and ∼P4.5. Lumen formation at E14.5 was advanced in Slc26a4−/− mice compared to Slc26a4+/− littermates (Fig. 4). The cochlear lumen increased with development in Slc26a4+/− and Slc26a4−/− mice (Fig. 5). The ratio between the luminal size in Slc26a4+/− and Slc26a4−/− increase from factor 6 at E16.5 to factor 12 at E18.5.


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)

Cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice.A, D and G: Luminal area measurements of cross-section #1 in cochleae obtained from E14.5, E16.5 and E18.5 littermates, respectively. The number next to the bars represents the N number of animals. Significant differences are marked (*). B and C, cochlear cross-sections of E14.5 Slc26a4+/− and Slc26a4−/− littermates. E and F, cochlear cross-sections of E16.5 Slc26a4+/− and Slc26a4−/− littermates. H and I, cochlear cross-sections of E18.5 Slc26a4+/− and Slc26a4−/− littermates. Scala media was highlighted in pink. Images without the pink overlay are available in Figure S1 (Supporting information). Arrows point to cross-section #1, which was used for digital area measurements. F-actin (green) was labeled. Cochlear cross-sections were imaged by laser-scanning microscopy.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2984494&req=5

pone-0014041-g004: Cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice.A, D and G: Luminal area measurements of cross-section #1 in cochleae obtained from E14.5, E16.5 and E18.5 littermates, respectively. The number next to the bars represents the N number of animals. Significant differences are marked (*). B and C, cochlear cross-sections of E14.5 Slc26a4+/− and Slc26a4−/− littermates. E and F, cochlear cross-sections of E16.5 Slc26a4+/− and Slc26a4−/− littermates. H and I, cochlear cross-sections of E18.5 Slc26a4+/− and Slc26a4−/− littermates. Scala media was highlighted in pink. Images without the pink overlay are available in Figure S1 (Supporting information). Arrows point to cross-section #1, which was used for digital area measurements. F-actin (green) was labeled. Cochlear cross-sections were imaged by laser-scanning microscopy.
Mentions: In a second set of experiments, we compared the onset of cochlear lumen formation in Slc26a4+/− and Slc26a4−/− mice and monitored the progression of the enlargement between E14.5 and ∼P4.5. Lumen formation at E14.5 was advanced in Slc26a4−/− mice compared to Slc26a4+/− littermates (Fig. 4). The cochlear lumen increased with development in Slc26a4+/− and Slc26a4−/− mice (Fig. 5). The ratio between the luminal size in Slc26a4+/− and Slc26a4−/− increase from factor 6 at E16.5 to factor 12 at E18.5.

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