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Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss

Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusi...

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Autores principales: Chen, Jing, Ingham, Neil, Kelly, John, Jadeja, Shalini, Goulding, David, Pass, Johanna, Mahajan, Vinit B., Tsang, Stephen H., Nijnik, Anastasia, Jackson, Ian J., White, Jacqueline K., Forge, Andrew, Jagger, Daniel, Steel, Karen P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214598/
https://www.ncbi.nlm.nih.gov/pubmed/25356849
http://dx.doi.org/10.1371/journal.pgen.1004688
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author Chen, Jing
Ingham, Neil
Kelly, John
Jadeja, Shalini
Goulding, David
Pass, Johanna
Mahajan, Vinit B.
Tsang, Stephen H.
Nijnik, Anastasia
Jackson, Ian J.
White, Jacqueline K.
Forge, Andrew
Jagger, Daniel
Steel, Karen P.
author_facet Chen, Jing
Ingham, Neil
Kelly, John
Jadeja, Shalini
Goulding, David
Pass, Johanna
Mahajan, Vinit B.
Tsang, Stephen H.
Nijnik, Anastasia
Jackson, Ian J.
White, Jacqueline K.
Forge, Andrew
Jagger, Daniel
Steel, Karen P.
author_sort Chen, Jing
collection PubMed
description Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing.
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spelling pubmed-42145982014-11-05 Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss Chen, Jing Ingham, Neil Kelly, John Jadeja, Shalini Goulding, David Pass, Johanna Mahajan, Vinit B. Tsang, Stephen H. Nijnik, Anastasia Jackson, Ian J. White, Jacqueline K. Forge, Andrew Jagger, Daniel Steel, Karen P. PLoS Genet Research Article Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing. Public Library of Science 2014-10-30 /pmc/articles/PMC4214598/ /pubmed/25356849 http://dx.doi.org/10.1371/journal.pgen.1004688 Text en © 2014 Chen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chen, Jing
Ingham, Neil
Kelly, John
Jadeja, Shalini
Goulding, David
Pass, Johanna
Mahajan, Vinit B.
Tsang, Stephen H.
Nijnik, Anastasia
Jackson, Ian J.
White, Jacqueline K.
Forge, Andrew
Jagger, Daniel
Steel, Karen P.
Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title_full Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title_fullStr Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title_full_unstemmed Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title_short Spinster Homolog 2 (Spns2) Deficiency Causes Early Onset Progressive Hearing Loss
title_sort spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214598/
https://www.ncbi.nlm.nih.gov/pubmed/25356849
http://dx.doi.org/10.1371/journal.pgen.1004688
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