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The Journal of Neuroscience, December 13, 2006, 26(50):13076-13088; doi:10.1523/JNEUROSCI.3746-06.2006

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Cellular/Molecular
Progressive Deafness and Altered Cochlear Innervation in Knock-Out Mice Lacking Prosaposin

Omar Akil,¹ Jolie Chang,¹ Hakim Hiel,² Jee-Hyun Kong,³ Eunyoung Yi,² Elisabeth Glowatzki,² and Lawrence R. Lustig¹

¹Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco, San Francisco, California 94143-0449, ²Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, and ³Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Lawrence R. Lustig, Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco, U401, Box 0449, 533 Parnassus Avenue, San Francisco, CA 94143-0449. Email: llustig{at}ohns.ucsf.edu

After a yeast two-hybrid screen identified prosaposin as a potential interacting protein with the nicotinic acetylcholine receptor (nAChR) subunit 10, studies were performed to characterize prosaposin in the normal rodent inner ear. Prosaposin demonstrates diffuse organ of Corti expression at birth, with gradual localization to the inner hair cells (IHCs) and its supporting cells, inner pillar cells, and synaptic region of the outer hair cells (OHCs) and Deiters' cells (DCs) by postnatal day 21 (P21). Microdissected OHC and DC quantitative reverse transcriptase-PCR and immunohistology localizes prosaposin mRNA to DCs and OHCs, and protein predominantly to the apex of the DCs. Subsequent studies in a prosaposin knock-out (KO) (–/–) mouse showed intact but slightly reduced hearing through P19, but deafness by P25 and reduced distortion product otoacoustic emissions from P15 onward. Beginning at P12, the prosaposin KO mice showed histologic organ of Corti changes including cellular hypertrophy in the region of the IHC and greater epithelial ridge, a loss of OHCs from cochlear apex, and vacuolization of OHCs. Immunofluorescence revealed exuberant overgrowth of auditory afferent neurites in the region of the IHCs and proliferation of auditory efferent neurites in the region of the tunnel of Corti. IHC recordings from these KO mice showed normal I–V curves and responses to applied acetylcholine. Together, these results suggest that prosaposin helps maintain normal innervation patterns to the organ of Corti. Furthermore, prosaposin's overlapping developmental expression pattern and binding capacity toward the nAChR 10 suggest that 10 may also play a role in this function.

Key words: acetylcholine receptor; AchR; afferent; auditory; auditory nerve; cochlea; development; efferent; hair cells; neurotropic; nicotinic receptor; prosaposin; saposin

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Received Feb. 17, 2005; revised Nov. 10, 2006; accepted Nov. 13, 2006.

Correspondence should be addressed to Lawrence R. Lustig, Department of Otolaryngology–Head and Neck Surgery, University of California, San Francisco, U401, Box 0449, 533 Parnassus Avenue, San Francisco, CA 94143-0449. Email: llustig{at}ohns.ucsf.edu

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