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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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Pathological changes in stria vascularis and normal position of Reissner's membrane.A,B In semi-thin sections (P28), the position of Reissner's membrane is not changed (bold arrow). Hair cells and supporting cells of the most basal turn have degenerated (open arrow). The neural dendrites in Rosenthal's canal appeared reduced (arrow). Scale bar: 100 µm. C and D are expanded views of the areas framed in A and B and display similar morphology of fibrocytes in mutants and controls. Scale bar 20 µm. By transmission electron microscopy (P28, E–I), the normal scallop-shaped (bold arrow) luminal boundary of marginal cells in control mice (E) was not found in the Spns2tm1a/tm1a mice (F). Abnormalities were seen in nuclei of endothelial cells (EC) and pericytes (PC) in strial capillaries of Spns2tm1a/tm1a mice (G,H), which were not seen in the capillaries of spiral ligament (I) and control strial capillaries (E). Scale bars: 10 µm in E,F, 2 µm in G–I.
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pgen-1004688-g006: Pathological changes in stria vascularis and normal position of Reissner's membrane.A,B In semi-thin sections (P28), the position of Reissner's membrane is not changed (bold arrow). Hair cells and supporting cells of the most basal turn have degenerated (open arrow). The neural dendrites in Rosenthal's canal appeared reduced (arrow). Scale bar: 100 µm. C and D are expanded views of the areas framed in A and B and display similar morphology of fibrocytes in mutants and controls. Scale bar 20 µm. By transmission electron microscopy (P28, E–I), the normal scallop-shaped (bold arrow) luminal boundary of marginal cells in control mice (E) was not found in the Spns2tm1a/tm1a mice (F). Abnormalities were seen in nuclei of endothelial cells (EC) and pericytes (PC) in strial capillaries of Spns2tm1a/tm1a mice (G,H), which were not seen in the capillaries of spiral ligament (I) and control strial capillaries (E). Scale bars: 10 µm in E,F, 2 µm in G–I.

Mentions: We analysed the structure of the lateral wall of the cochlea, including the stria vascularis and spiral ligament, using semithin sections and transmission electron microscopy in P28 mice. The position of Reissner's membrane was normal in semi-thin sections of P28 cochleae (Fig. 6A,B), with no evidence of hydrops or collapse. No systematic differences in the appearance of fibrocytes of the spiral ligament were observed (Fig. 6C,D). The inner boundaries of marginal cells of the stria, facing the endolymph, have a typical scallop-shaped surface in wildtype mice with the junctions between adjacent cells raised, but this feature was not seen in the Spns2tm1a/tm1a mice and the luminal surface appeared flat (Fig. 6E,F). Nuclei of marginal and basal cells appeared more rounded in Spns2tm1a/tm1a mice than in wildtypes (Fig. 6E,F). There was also a marked difference in the appearance of endothelial cells and pericytes [25], [26] of strial capillaries, with the nuclei of mutant cells appearing more darkly-stained (Fig. 6G,H). However, this abnormality appeared to be limited to capillaries of the stria vascularis only, and was not seen in the spiral ligament capillaries (Fig. 6I), suggesting a specific effect of Spns2 deficiency on the capillaries of the stria vascularis.


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)

Pathological changes in stria vascularis and normal position of Reissner's membrane.A,B In semi-thin sections (P28), the position of Reissner's membrane is not changed (bold arrow). Hair cells and supporting cells of the most basal turn have degenerated (open arrow). The neural dendrites in Rosenthal's canal appeared reduced (arrow). Scale bar: 100 µm. C and D are expanded views of the areas framed in A and B and display similar morphology of fibrocytes in mutants and controls. Scale bar 20 µm. By transmission electron microscopy (P28, E–I), the normal scallop-shaped (bold arrow) luminal boundary of marginal cells in control mice (E) was not found in the Spns2tm1a/tm1a mice (F). Abnormalities were seen in nuclei of endothelial cells (EC) and pericytes (PC) in strial capillaries of Spns2tm1a/tm1a mice (G,H), which were not seen in the capillaries of spiral ligament (I) and control strial capillaries (E). Scale bars: 10 µm in E,F, 2 µm in G–I.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4214598&req=5

pgen-1004688-g006: Pathological changes in stria vascularis and normal position of Reissner's membrane.A,B In semi-thin sections (P28), the position of Reissner's membrane is not changed (bold arrow). Hair cells and supporting cells of the most basal turn have degenerated (open arrow). The neural dendrites in Rosenthal's canal appeared reduced (arrow). Scale bar: 100 µm. C and D are expanded views of the areas framed in A and B and display similar morphology of fibrocytes in mutants and controls. Scale bar 20 µm. By transmission electron microscopy (P28, E–I), the normal scallop-shaped (bold arrow) luminal boundary of marginal cells in control mice (E) was not found in the Spns2tm1a/tm1a mice (F). Abnormalities were seen in nuclei of endothelial cells (EC) and pericytes (PC) in strial capillaries of Spns2tm1a/tm1a mice (G,H), which were not seen in the capillaries of spiral ligament (I) and control strial capillaries (E). Scale bars: 10 µm in E,F, 2 µm in G–I.
Mentions: We analysed the structure of the lateral wall of the cochlea, including the stria vascularis and spiral ligament, using semithin sections and transmission electron microscopy in P28 mice. The position of Reissner's membrane was normal in semi-thin sections of P28 cochleae (Fig. 6A,B), with no evidence of hydrops or collapse. No systematic differences in the appearance of fibrocytes of the spiral ligament were observed (Fig. 6C,D). The inner boundaries of marginal cells of the stria, facing the endolymph, have a typical scallop-shaped surface in wildtype mice with the junctions between adjacent cells raised, but this feature was not seen in the Spns2tm1a/tm1a mice and the luminal surface appeared flat (Fig. 6E,F). Nuclei of marginal and basal cells appeared more rounded in Spns2tm1a/tm1a mice than in wildtypes (Fig. 6E,F). There was also a marked difference in the appearance of endothelial cells and pericytes [25], [26] of strial capillaries, with the nuclei of mutant cells appearing more darkly-stained (Fig. 6G,H). However, this abnormality appeared to be limited to capillaries of the stria vascularis only, and was not seen in the spiral ligament capillaries (Fig. 6I), suggesting a specific effect of Spns2 deficiency on the capillaries of the stria vascularis.

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