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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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ABR thresholds and SEM assessment suggest a local function of Spns2 in the inner ear.ABR thresholds (means +/−SD) are shown for homozygotes (red), heterozygotes (blue) and wildtypes (green), aged 7–14 weeks. Mice homozygous for the Spns2tm1a allele displayed elevated ABR thresholds and degeneration of hair cells (A left, 4 wks and B). By crossing with mice expressing Flp recombinase to excise the inserted cassette, Spns2tm1c/tm1c mice were produced, which had normal ABR thresholds and normal hair cell morphology (A middle, 8 wks and C). Then Spns2tm1c/tm1c were crossed with Sox10-Cre mice to produce Spns2tm1d/tm1d;Sox10-Cre mice which showed no response up to 95 dB SPL and hair cell degeneration with bulges and holes in the reticular lamina (A right, 4 wks and D). SEM images are taken from the middle turn (40–70%) of the cochlea. Scale bar: 10 µm in B,C,D.
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pgen-1004688-g009: ABR thresholds and SEM assessment suggest a local function of Spns2 in the inner ear.ABR thresholds (means +/−SD) are shown for homozygotes (red), heterozygotes (blue) and wildtypes (green), aged 7–14 weeks. Mice homozygous for the Spns2tm1a allele displayed elevated ABR thresholds and degeneration of hair cells (A left, 4 wks and B). By crossing with mice expressing Flp recombinase to excise the inserted cassette, Spns2tm1c/tm1c mice were produced, which had normal ABR thresholds and normal hair cell morphology (A middle, 8 wks and C). Then Spns2tm1c/tm1c were crossed with Sox10-Cre mice to produce Spns2tm1d/tm1d;Sox10-Cre mice which showed no response up to 95 dB SPL and hair cell degeneration with bulges and holes in the reticular lamina (A right, 4 wks and D). SEM images are taken from the middle turn (40–70%) of the cochlea. Scale bar: 10 µm in B,C,D.

Mentions: We generated the conditional allele of Spns2 (Spns2tm1c) by crossing the Spns2tm1a allele to a line expressing Flp recombinase to excise the inserted cassette (Fig. 1A). The Spns2tm1c/tm1c mice have the same Spns2 allele as the wildtype except that exon 3 is flanked by two loxP sites. Spns2tm1c/tm1c mice showed normal ABR thresholds and normal morphology of hair cells (Fig. 9A, C). These observations confirmed that the inner ear defects we found in the Spns2tm1a/tm1a mice were due to the insertion of the cassette and its disruption of Spns2 gene function.


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)

ABR thresholds and SEM assessment suggest a local function of Spns2 in the inner ear.ABR thresholds (means +/−SD) are shown for homozygotes (red), heterozygotes (blue) and wildtypes (green), aged 7–14 weeks. Mice homozygous for the Spns2tm1a allele displayed elevated ABR thresholds and degeneration of hair cells (A left, 4 wks and B). By crossing with mice expressing Flp recombinase to excise the inserted cassette, Spns2tm1c/tm1c mice were produced, which had normal ABR thresholds and normal hair cell morphology (A middle, 8 wks and C). Then Spns2tm1c/tm1c were crossed with Sox10-Cre mice to produce Spns2tm1d/tm1d;Sox10-Cre mice which showed no response up to 95 dB SPL and hair cell degeneration with bulges and holes in the reticular lamina (A right, 4 wks and D). SEM images are taken from the middle turn (40–70%) of the cochlea. Scale bar: 10 µm in B,C,D.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004688-g009: ABR thresholds and SEM assessment suggest a local function of Spns2 in the inner ear.ABR thresholds (means +/−SD) are shown for homozygotes (red), heterozygotes (blue) and wildtypes (green), aged 7–14 weeks. Mice homozygous for the Spns2tm1a allele displayed elevated ABR thresholds and degeneration of hair cells (A left, 4 wks and B). By crossing with mice expressing Flp recombinase to excise the inserted cassette, Spns2tm1c/tm1c mice were produced, which had normal ABR thresholds and normal hair cell morphology (A middle, 8 wks and C). Then Spns2tm1c/tm1c were crossed with Sox10-Cre mice to produce Spns2tm1d/tm1d;Sox10-Cre mice which showed no response up to 95 dB SPL and hair cell degeneration with bulges and holes in the reticular lamina (A right, 4 wks and D). SEM images are taken from the middle turn (40–70%) of the cochlea. Scale bar: 10 µm in B,C,D.
Mentions: We generated the conditional allele of Spns2 (Spns2tm1c) by crossing the Spns2tm1a allele to a line expressing Flp recombinase to excise the inserted cassette (Fig. 1A). The Spns2tm1c/tm1c mice have the same Spns2 allele as the wildtype except that exon 3 is flanked by two loxP sites. Spns2tm1c/tm1c mice showed normal ABR thresholds and normal morphology of hair cells (Fig. 9A, C). These observations confirmed that the inner ear defects we found in the Spns2tm1a/tm1a mice were due to the insertion of the cassette and its disruption of Spns2 gene function.

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