Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2

SLC44A2 ( s o l ute c arrier 44a2 ), also known as CTL2 ( c holine t ransporter- l ike protein 2 ), is expressed in many supporting cell types in the cochlea and is implicated in hair cell survival and antibody-induced hearing loss. In mice with the mixed C57BL/6-129 background, homozygous deletion of Slc44a2 exons 3–10 ( Slc44a2 Δ/Δ ) resulted in high-frequency hearing loss and hair cell death. To reduce effects associated with a ge- r elated h earing l oss (ARHL) in these strains, mice carrying the Slc44a2 Δ allele were backcrossed to the ARHL-resistant FVB/NJ strain and evaluated after backcross seven (N7) (99 % FVB). Slc44a2 Δ/Δ mice produced abnormally spliced Slc44a2 transcripts that contain a frameshift and premature stop codons. Neither full-length SLC44A2 nor a putative truncated protein could be detected in Slc44a2 Δ/Δ mice, suggesting a likely null allele. Auditory brain stem responses (ABRs) of mice carrying the Slc44a2 Δ allele on an FVB/NJ genetic background were tested longitudinally between the ages of 2 and 10 months. By 6 months of age, Slc44a2 Δ/Δ mice exhibited hearing loss at 32 kHz, but at 12 and 24 kHz had sound thresholds similar to those of wild-type Slc44a2 +/+ and heterozygous +/Slc44a2 Δ mice. After 6 months of age, Slc44a2 Δ/Δ mutants exhibited progressive hearing loss at all frequencies and +/Slc44a2 Δ mice exhibited moderate threshold elevations at high frequency. Histologic evaluation of Slc44a2 Δ/Δ mice revealed extensive hair cell and spiral ganglion cell loss, especially in the basal turn of the cochlea. We conclude that Slc44a2 function is required for long-term hair cell survival and maintenance of hearing.