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Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.

Chen J, Ingham N, Kelly J, Jadeja S, Goulding D, Pass J, Mahajan VB, Tsang SH, Nijnik A, Jackson IJ, White JK, Forge A, Jagger D, Steel KP - PLoS Genet. (2014)

Bottom Line: The mechanism of action of Spns2 is still elusive in mammals.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.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

ABSTRACT
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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Normal strial integrity and normal permeability of strial capillaries to BSA-FITC.A,B, Endolymphatic and perilymphatic compartments were perfused by Sulfo-NHS-LC-Biotin. Biotin was detected by FITC-conjugated streptavidin (green) in frozen sections of 6 week old mice. No sign of biotin entry into the stria vascularis compartment was found as shown by the arrow indicated that the tight junctions of marginal and basal cells are sealed in Spns2tm1a/tm1a mice (B) compared with the control mice (A). C,D, Stria vascularis capillaries of young adult wildtype (C) and Spns2tm1a/tm1a (D) mice following BSA-FITC injection into the tail vein, showing no evidence of leakage of the tracer (green) out of the capillaries. The increased branching of capillaries in these Spns2tm1a/tm1a mice is also visible. Scale bars, 20 µm in A–D.
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pgen-1004688-g007: Normal strial integrity and normal permeability of strial capillaries to BSA-FITC.A,B, Endolymphatic and perilymphatic compartments were perfused by Sulfo-NHS-LC-Biotin. Biotin was detected by FITC-conjugated streptavidin (green) in frozen sections of 6 week old mice. No sign of biotin entry into the stria vascularis compartment was found as shown by the arrow indicated that the tight junctions of marginal and basal cells are sealed in Spns2tm1a/tm1a mice (B) compared with the control mice (A). C,D, Stria vascularis capillaries of young adult wildtype (C) and Spns2tm1a/tm1a (D) mice following BSA-FITC injection into the tail vein, showing no evidence of leakage of the tracer (green) out of the capillaries. The increased branching of capillaries in these Spns2tm1a/tm1a mice is also visible. Scale bars, 20 µm in A–D.

Mentions: In view of the abnormal morphology of marginal cell boundaries, we asked whether the diffusion barrier of stria vascularis, for example between adjacent marginal cells, was affected because normal morphology of boundaries at P14 does not necessarily mean normal function. We used biotin as a tracer injected into the endolymphatic and perilymphatic compartments of 6 week old mice to test the barrier permeability of the stria vascularis. There was no evidence of biotin entry into the stria vascularis of Spns2tm1a/tm1a or control mice indicating a normal diffusion barrier of stria vascularis (Fig. 7A,B). As we observed dilated strial capillaries with abnormal endothelial cells and pericytes, we tested their permeability by injecting BSA-FITC into the tail vein. There were no signs of leakage of the tracer to the tissues surrounding the strial capillaries in Spns2tm1a/tm1a mice suggesting that they have normal permeability to BSA-FITC (Fig. 7C,D).


Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.

Chen J, Ingham N, Kelly J, Jadeja S, Goulding D, Pass J, Mahajan VB, Tsang SH, Nijnik A, Jackson IJ, White JK, Forge A, Jagger D, Steel KP - PLoS Genet. (2014)

Normal strial integrity and normal permeability of strial capillaries to BSA-FITC.A,B, Endolymphatic and perilymphatic compartments were perfused by Sulfo-NHS-LC-Biotin. Biotin was detected by FITC-conjugated streptavidin (green) in frozen sections of 6 week old mice. No sign of biotin entry into the stria vascularis compartment was found as shown by the arrow indicated that the tight junctions of marginal and basal cells are sealed in Spns2tm1a/tm1a mice (B) compared with the control mice (A). C,D, Stria vascularis capillaries of young adult wildtype (C) and Spns2tm1a/tm1a (D) mice following BSA-FITC injection into the tail vein, showing no evidence of leakage of the tracer (green) out of the capillaries. The increased branching of capillaries in these Spns2tm1a/tm1a mice is also visible. Scale bars, 20 µm in A–D.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4214598&req=5

pgen-1004688-g007: Normal strial integrity and normal permeability of strial capillaries to BSA-FITC.A,B, Endolymphatic and perilymphatic compartments were perfused by Sulfo-NHS-LC-Biotin. Biotin was detected by FITC-conjugated streptavidin (green) in frozen sections of 6 week old mice. No sign of biotin entry into the stria vascularis compartment was found as shown by the arrow indicated that the tight junctions of marginal and basal cells are sealed in Spns2tm1a/tm1a mice (B) compared with the control mice (A). C,D, Stria vascularis capillaries of young adult wildtype (C) and Spns2tm1a/tm1a (D) mice following BSA-FITC injection into the tail vein, showing no evidence of leakage of the tracer (green) out of the capillaries. The increased branching of capillaries in these Spns2tm1a/tm1a mice is also visible. Scale bars, 20 µm in A–D.
Mentions: In view of the abnormal morphology of marginal cell boundaries, we asked whether the diffusion barrier of stria vascularis, for example between adjacent marginal cells, was affected because normal morphology of boundaries at P14 does not necessarily mean normal function. We used biotin as a tracer injected into the endolymphatic and perilymphatic compartments of 6 week old mice to test the barrier permeability of the stria vascularis. There was no evidence of biotin entry into the stria vascularis of Spns2tm1a/tm1a or control mice indicating a normal diffusion barrier of stria vascularis (Fig. 7A,B). As we observed dilated strial capillaries with abnormal endothelial cells and pericytes, we tested their permeability by injecting BSA-FITC into the tail vein. There were no signs of leakage of the tracer to the tissues surrounding the strial capillaries in Spns2tm1a/tm1a mice suggesting that they have normal permeability to BSA-FITC (Fig. 7C,D).

Bottom Line: The mechanism of action of Spns2 is still elusive in mammals.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.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus