title: Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Ingham
authors.affiliation: Centre for Auditory Research, UCL Ear Institute, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Kelly
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom, and Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jadeja
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Goulding
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pass
authors.affiliation: Omics Laboratory, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.affiliation: Edward S. Harkness Eye Institute, Columbia University, New York, New York, United States of America.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Department of Physiology, Complex Traits Group, McGill University, Montreal, Quebec, Canada.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
authors.affiliation: MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom, and Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jackson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.affiliation: Centre for Auditory Research, UCL Ear Institute, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Forge
authors.affiliation: Centre for Auditory Research, UCL Ear Institute, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jagger
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
mesh_terms: D017668:Age of Onset; D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000869:Anterior Eye Segment / Q000378:metabolism / Q000473:pathology; D003051:Cochlea / Q000378:metabolism / Q000473:pathology*; D000072259:Connexin 26; D017630:Connexins; D007758:Ear, Inner / Q000473:pathology*; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000473:pathology; D034381:Hearing Loss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D038081:Organogenesis / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013316:Stria Vascularis / Q000473:pathology; D015027:Zebrafish
chemical_list: D027321:Anion Transport Proteins; D017630:Connexins; C000607042:GJB2 protein, human; D008246:Lysophospholipids; C000598727:Spns2 protein, human; D000072259:Connexin 26; C060506:sphingosine 1-phosphate; D013110:Sphingosine