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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 of mice with Spns2 conditionally inactivated in different tissues.ABR thresholds of individual mice are shown. All Cre driver lines showed normal thresholds (left column, in black. n = number of wildtype; number of mice carrying Cre). Most control littermates had normal responses (middle column: heterozygotes in blue; wildtypes in green). Homozygous Spns2tm1d mutants (red) carrying the relevant Cre alleles are shown in the right column. Spns2tm1d homozygotes carrying the Sox10-Cre allele had raised thresholds (top right), but the other four Cre lines had normal thresholds. The bottom row shows equivalent threshold data for the Spns2tm1c allele and the Flp recombinase line used to generate this allele, again showing normal thresholds. There were three exceptions of individuals with raised thresholds (one heterozygote each in Pf4-Cre cross and Tie1-Cre cross, one homozygote in Tie1-Cre cross), which we believe probably carry an independent mutation causing the impairment (subject to ongoing positional cloning study).
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pgen-1004688-g010: ABR thresholds of mice with Spns2 conditionally inactivated in different tissues.ABR thresholds of individual mice are shown. All Cre driver lines showed normal thresholds (left column, in black. n = number of wildtype; number of mice carrying Cre). Most control littermates had normal responses (middle column: heterozygotes in blue; wildtypes in green). Homozygous Spns2tm1d mutants (red) carrying the relevant Cre alleles are shown in the right column. Spns2tm1d homozygotes carrying the Sox10-Cre allele had raised thresholds (top right), but the other four Cre lines had normal thresholds. The bottom row shows equivalent threshold data for the Spns2tm1c allele and the Flp recombinase line used to generate this allele, again showing normal thresholds. There were three exceptions of individuals with raised thresholds (one heterozygote each in Pf4-Cre cross and Tie1-Cre cross, one homozygote in Tie1-Cre cross), which we believe probably carry an independent mutation causing the impairment (subject to ongoing positional cloning study).

Mentions: We then asked whether the hearing defects of Spns2tm1a/tm1a mice are caused by localised deficiency of Spns2 in the inner ear or are mediated systemically. S1P is known to be released from several other tissues that could affect cochlear function, including various blood cell types and endothelial cells [1], [2]. We generated conditional knockout mice carrying the Spns2tm1d allele in specific tissues by crossing mice carrying the Spns2tm1c allele with mice carrying Cre recombinase under the control of five different promoters: Tie1, Pf4, Lyve1, EpoR and Sox10, driving expression of Cre recombinase in blood vessel endothelial cells, platelets, lymphatic endothelial cells, red blood cells, and the inner ear with surrounding neural crest-derived mesenchyme respectively. Sox10-Cre transgenic mice have been successfully used to express Cre recombinase in the developing inner ear previously [31]. Homozygous Spns2tm1d mutants carrying the Tie1, Pf4, Lyve1 and EpoR Cre alleles all had normal ABR thresholds in young adults (Fig. 10). In contrast, no ABR response was detected in the young adult Spns2tm1d/tm1d;Sox10-Cre mice (Fig. 10). Spns2tm1d/tm1d; Sox10-Cre mice showed a similar pattern of progression of raised thresholds between 2 and 3 weeks old as observed in Spns2tm1a/tm1a mice (Fig. 11). Spns2tm1d/tm1d; Sox10-Cre mice also showed similar inner ear pathological changes as found in Spns2tm1a/tm1a mice, such as degeneration of hair cells (Fig. 9B, D) and irregular arrangement of marginal cell boundaries. Therefore, we propose that Spns2 plays an important role in mammalian hearing through its localised function in the inner ear.


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 of mice with Spns2 conditionally inactivated in different tissues.ABR thresholds of individual mice are shown. All Cre driver lines showed normal thresholds (left column, in black. n = number of wildtype; number of mice carrying Cre). Most control littermates had normal responses (middle column: heterozygotes in blue; wildtypes in green). Homozygous Spns2tm1d mutants (red) carrying the relevant Cre alleles are shown in the right column. Spns2tm1d homozygotes carrying the Sox10-Cre allele had raised thresholds (top right), but the other four Cre lines had normal thresholds. The bottom row shows equivalent threshold data for the Spns2tm1c allele and the Flp recombinase line used to generate this allele, again showing normal thresholds. There were three exceptions of individuals with raised thresholds (one heterozygote each in Pf4-Cre cross and Tie1-Cre cross, one homozygote in Tie1-Cre cross), which we believe probably carry an independent mutation causing the impairment (subject to ongoing positional cloning study).
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004688-g010: ABR thresholds of mice with Spns2 conditionally inactivated in different tissues.ABR thresholds of individual mice are shown. All Cre driver lines showed normal thresholds (left column, in black. n = number of wildtype; number of mice carrying Cre). Most control littermates had normal responses (middle column: heterozygotes in blue; wildtypes in green). Homozygous Spns2tm1d mutants (red) carrying the relevant Cre alleles are shown in the right column. Spns2tm1d homozygotes carrying the Sox10-Cre allele had raised thresholds (top right), but the other four Cre lines had normal thresholds. The bottom row shows equivalent threshold data for the Spns2tm1c allele and the Flp recombinase line used to generate this allele, again showing normal thresholds. There were three exceptions of individuals with raised thresholds (one heterozygote each in Pf4-Cre cross and Tie1-Cre cross, one homozygote in Tie1-Cre cross), which we believe probably carry an independent mutation causing the impairment (subject to ongoing positional cloning study).
Mentions: We then asked whether the hearing defects of Spns2tm1a/tm1a mice are caused by localised deficiency of Spns2 in the inner ear or are mediated systemically. S1P is known to be released from several other tissues that could affect cochlear function, including various blood cell types and endothelial cells [1], [2]. We generated conditional knockout mice carrying the Spns2tm1d allele in specific tissues by crossing mice carrying the Spns2tm1c allele with mice carrying Cre recombinase under the control of five different promoters: Tie1, Pf4, Lyve1, EpoR and Sox10, driving expression of Cre recombinase in blood vessel endothelial cells, platelets, lymphatic endothelial cells, red blood cells, and the inner ear with surrounding neural crest-derived mesenchyme respectively. Sox10-Cre transgenic mice have been successfully used to express Cre recombinase in the developing inner ear previously [31]. Homozygous Spns2tm1d mutants carrying the Tie1, Pf4, Lyve1 and EpoR Cre alleles all had normal ABR thresholds in young adults (Fig. 10). In contrast, no ABR response was detected in the young adult Spns2tm1d/tm1d;Sox10-Cre mice (Fig. 10). Spns2tm1d/tm1d; Sox10-Cre mice showed a similar pattern of progression of raised thresholds between 2 and 3 weeks old as observed in Spns2tm1a/tm1a mice (Fig. 11). Spns2tm1d/tm1d; Sox10-Cre mice also showed similar inner ear pathological changes as found in Spns2tm1a/tm1a mice, such as degeneration of hair cells (Fig. 9B, D) and irregular arrangement of marginal cell boundaries. Therefore, we propose that Spns2 plays an important role in mammalian hearing through its localised function in the inner ear.

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