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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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Endocochlear potential (EP) showed a progressive reduction from P14 to P21.Control mice had normal EP magnitudes of around 99ā€“120 mV at P14 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š9), P21 (Spns2+/+, nā€Š=ā€Š3; Spns2+/tm1a, nā€Š=ā€Š3) and P28 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š5). The Spns2tm1a/tm1a mice showed a significant reduction in the EP magnitude at P14 (nā€Š=ā€Š11; p<0.001), P21 (nā€Š=ā€Š6; pā€Š=ā€Š0.002) and P28 (nā€Š=ā€Š12; p<0.001) compared to age-matched control values (Mann-Whitney Rank Sum Test; SigmaPlot v12.0). There was a large drop in the EP values in Spns2tm1a/tm1a mice between P14 and P21.
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pgen-1004688-g004: Endocochlear potential (EP) showed a progressive reduction from P14 to P21.Control mice had normal EP magnitudes of around 99ā€“120 mV at P14 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š9), P21 (Spns2+/+, nā€Š=ā€Š3; Spns2+/tm1a, nā€Š=ā€Š3) and P28 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š5). The Spns2tm1a/tm1a mice showed a significant reduction in the EP magnitude at P14 (nā€Š=ā€Š11; p<0.001), P21 (nā€Š=ā€Š6; pā€Š=ā€Š0.002) and P28 (nā€Š=ā€Š12; p<0.001) compared to age-matched control values (Mann-Whitney Rank Sum Test; SigmaPlot v12.0). There was a large drop in the EP values in Spns2tm1a/tm1a mice between P14 and P21.

Mentions: The stria vascularis is responsible for pumping K+ into the endolymph and generation of the endocochlear potential (EP) [23]. The EP starts to develop at around P6 in the mouse reaching adult values around P16 [24] and plays a key role in sound transduction because it provides approximately half of the electrochemical gradient that drives cations from the endolymph, a K+-rich extracellular fluid, into the sensory hair cells through mechanoelectrical transduction channels. The lateral wall of the cochlea is composed of the stria vascularis, spiral prominence and the spiral ligament. A defect in the function of any of these components could interfere with the generation of the EP. Therefore, we measured the EP to evaluate the function of the lateral wall. The EP values of the control mice were normal, around 99 to 120 mV, which matched their normal hearing. Spns2tm1a/tm1a mice had abnormally low EP values of 2 to 41 mV at both P21 and P28 when they were profoundly deaf (Fig. 4). However, at P14 the EP was higher, ranging from 52 to 107 mV, with some measurements within the normal range, corresponding to the partially preserved hearing at that age (Fig. 1C). The EP appeared to develop to near-normal levels and then declined very rapidly between P14 and P21. These data indicate that the cause of hearing loss in Spns2tm1a/tm1a mice is a failure to maintain the normal level of the EP after it develops, suggesting that the primary lesion is more likely to be in the lateral wall than the organ of Corti.


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)

Endocochlear potential (EP) showed a progressive reduction from P14 to P21.Control mice had normal EP magnitudes of around 99ā€“120 mV at P14 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š9), P21 (Spns2+/+, nā€Š=ā€Š3; Spns2+/tm1a, nā€Š=ā€Š3) and P28 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š5). The Spns2tm1a/tm1a mice showed a significant reduction in the EP magnitude at P14 (nā€Š=ā€Š11; p<0.001), P21 (nā€Š=ā€Š6; pā€Š=ā€Š0.002) and P28 (nā€Š=ā€Š12; p<0.001) compared to age-matched control values (Mann-Whitney Rank Sum Test; SigmaPlot v12.0). There was a large drop in the EP values in Spns2tm1a/tm1a mice between P14 and P21.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004688-g004: Endocochlear potential (EP) showed a progressive reduction from P14 to P21.Control mice had normal EP magnitudes of around 99ā€“120 mV at P14 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š9), P21 (Spns2+/+, nā€Š=ā€Š3; Spns2+/tm1a, nā€Š=ā€Š3) and P28 (Spns2+/+, nā€Š=ā€Š4; Spns2+/tm1a, nā€Š=ā€Š5). The Spns2tm1a/tm1a mice showed a significant reduction in the EP magnitude at P14 (nā€Š=ā€Š11; p<0.001), P21 (nā€Š=ā€Š6; pā€Š=ā€Š0.002) and P28 (nā€Š=ā€Š12; p<0.001) compared to age-matched control values (Mann-Whitney Rank Sum Test; SigmaPlot v12.0). There was a large drop in the EP values in Spns2tm1a/tm1a mice between P14 and P21.
Mentions: The stria vascularis is responsible for pumping K+ into the endolymph and generation of the endocochlear potential (EP) [23]. The EP starts to develop at around P6 in the mouse reaching adult values around P16 [24] and plays a key role in sound transduction because it provides approximately half of the electrochemical gradient that drives cations from the endolymph, a K+-rich extracellular fluid, into the sensory hair cells through mechanoelectrical transduction channels. The lateral wall of the cochlea is composed of the stria vascularis, spiral prominence and the spiral ligament. A defect in the function of any of these components could interfere with the generation of the EP. Therefore, we measured the EP to evaluate the function of the lateral wall. The EP values of the control mice were normal, around 99 to 120 mV, which matched their normal hearing. Spns2tm1a/tm1a mice had abnormally low EP values of 2 to 41 mV at both P21 and P28 when they were profoundly deaf (Fig. 4). However, at P14 the EP was higher, ranging from 52 to 107 mV, with some measurements within the normal range, corresponding to the partially preserved hearing at that age (Fig. 1C). The EP appeared to develop to near-normal levels and then declined very rapidly between P14 and P21. These data indicate that the cause of hearing loss in Spns2tm1a/tm1a mice is a failure to maintain the normal level of the EP after it develops, suggesting that the primary lesion is more likely to be in the lateral wall than the organ of Corti.

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