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

Autor: Bala Naveen Kakaraparthi, Thankam S. Nair, Kelli Rule, Susan G. Fisher, Mark J. Hoenerhoff, Trey B. Thomas, Lisa L. Kabara, Richard A. Altschuler, Lillian Lu, Thomas L. Saunders, David F. Dolan, Maria M. Galano, Thomas E. Carey, Ariane Kanicki, Danielle M. Miller, Pavan K. Kommareddi, Elizabeth D. Hughes, Irina Laczkovich, David C. Kohrman, Julie M. Jones
Rok vydání: 2015
Předmět:
Male
Hearing loss
Hearing Loss
Sensorineural
Molecular Sequence Data
choline transporter-like protein 2
Mice
Transgenic
Biology
hair cell loss
Frameshift mutation
03 medical and health sciences
0302 clinical medicine
murine gene knockout
Hair Cells
Auditory
otorhinolaryngologic diseases
medicine
Animals
Amino Acid Sequence
spiral ganglion cell loss
Allele
Cochlea
Spiral ganglion
030304 developmental biology
Genetics
0303 health sciences
Membrane Transport Proteins
auditory brain stem responses
medicine.disease
Molecular biology
Null allele
Sensory Systems
Mice
Inbred C57BL
medicine.anatomical_structure
Otorhinolaryngology
solute carrier protein 44a2
Female
Sensorineural hearing loss
supporting cells
Hair cell
medicine.symptom
Spiral Ganglion
Gene Deletion
030217 neurology & neurosurgery
Research Article
Zdroj: JARO: Journal of the Association for Research in Otolaryngology
ISSN: 1438-7573
1525-3961
DOI: 10.1007/s10162-015-0547-3
Popis: SLC44A2 (solute carrier 44a2), also known as CTL2 (choline transporter-like 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 age-related hearing loss (ARHL) in these strains, mice carrying the Slc44a2Δ 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 frame shift 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 Slc44a2Δ 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 +/Slc44a2Δ 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.
Databáze: OpenAIRE
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