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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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Related in: MedlinePlus

Progressive deterioration of hair cells shown by scanning electron microscopy.Spns2tm1a/tm1a mice have a normal structure of hair bundles compared with wildtype mice at P21 (A,B). Scattered or patchy outer hair cell (OHC) degeneration was observed in the middle turn at P28 (C,D). Most stereocilia of OHCs in basal and middle turn have degenerated and stereocilia of IHCs were fused or lost at P56 (E,F). All the images were taken from the middle turn of the cochlea, defined as 40–70% of the distance along the cochlear duct from the base. Scale bar: 10 µm.
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pgen-1004688-g003: Progressive deterioration of hair cells shown by scanning electron microscopy.Spns2tm1a/tm1a mice have a normal structure of hair bundles compared with wildtype mice at P21 (A,B). Scattered or patchy outer hair cell (OHC) degeneration was observed in the middle turn at P28 (C,D). Most stereocilia of OHCs in basal and middle turn have degenerated and stereocilia of IHCs were fused or lost at P56 (E,F). All the images were taken from the middle turn of the cochlea, defined as 40–70% of the distance along the cochlear duct from the base. Scale bar: 10 µm.

Mentions: The Spns2tm1a/tm1a mice showed a normal gross morphology of the middle ear and ossicles assessed by dissection and gross inspection, and the cleared inner ears also showed no malformation (Fig. S1C,D). We performed scanning electron microscopy (SEM) of P4, P21, P28 and P56 Spns2tm1a/tm1a mice and littermate controls. The hair cells of Spns2tm1a/tm1a mice appeared normal at P4 (Fig. S1E,F) and at P21 (Fig. 3A,B). There was scattered or patchy degeneration of stereocilia of outer hair cells in the homozygous cochleae at P28 (Fig. 3C,D). Hair cell degeneration became more apparent over time and by P56, only a few outer hair cells remained at the apex with most of them missing in other turns, and inner hair cells showed signs of degeneration such as fused stereocilia (Fig. 3E,F).


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)

Progressive deterioration of hair cells shown by scanning electron microscopy.Spns2tm1a/tm1a mice have a normal structure of hair bundles compared with wildtype mice at P21 (A,B). Scattered or patchy outer hair cell (OHC) degeneration was observed in the middle turn at P28 (C,D). Most stereocilia of OHCs in basal and middle turn have degenerated and stereocilia of IHCs were fused or lost at P56 (E,F). All the images were taken from the middle turn of the cochlea, defined as 40–70% of the distance along the cochlear duct from the base. Scale bar: 10 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004688-g003: Progressive deterioration of hair cells shown by scanning electron microscopy.Spns2tm1a/tm1a mice have a normal structure of hair bundles compared with wildtype mice at P21 (A,B). Scattered or patchy outer hair cell (OHC) degeneration was observed in the middle turn at P28 (C,D). Most stereocilia of OHCs in basal and middle turn have degenerated and stereocilia of IHCs were fused or lost at P56 (E,F). All the images were taken from the middle turn of the cochlea, defined as 40–70% of the distance along the cochlear duct from the base. Scale bar: 10 µm.
Mentions: The Spns2tm1a/tm1a mice showed a normal gross morphology of the middle ear and ossicles assessed by dissection and gross inspection, and the cleared inner ears also showed no malformation (Fig. S1C,D). We performed scanning electron microscopy (SEM) of P4, P21, P28 and P56 Spns2tm1a/tm1a mice and littermate controls. The hair cells of Spns2tm1a/tm1a mice appeared normal at P4 (Fig. S1E,F) and at P21 (Fig. 3A,B). There was scattered or patchy degeneration of stereocilia of outer hair cells in the homozygous cochleae at P28 (Fig. 3C,D). Hair cell degeneration became more apparent over time and by P56, only a few outer hair cells remained at the apex with most of them missing in other turns, and inner hair cells showed signs of degeneration such as fused stereocilia (Fig. 3E,F).

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