Age-related hearing loss and the ahl locus in mice
Introduction
The C57BL/6 inbred strain of mice, hereafter referred to as B6, was found to have age-related hearing loss (Mikaelian, 1979, Henry and Chole, 1980) and has been used in many studies to evaluate cochlear structure and function (Willott, 1986, Willott et al., 1988, Willott, 1991, Hultcrantz and Li, 1993, White et al., 2000, McFadden et al., 2001, Bartolome et al., 2001). Cochleae of these mice are characterized by early degeneration of outer hair cells and spiral ganglion cells and ultimately by the degeneration of the entire organ of Corti and most of the spiral ganglion cells in the basal turn. The phenotype is similar to that seen in some humans with presbycusis in which the basal turn of the cochlea is degenerated (Schuknecht and Gacek, 1993), and it was assumed that by studying cochlear pathology insight would be gained about the mechanisms of age-related hearing loss. Recently Hequembourg and Liberman (2001) provided evidence that the cellular origin of the cochlear degeneration might be the early degeneration of the type IV fibrocytes in the spiral ligament. The loss of these cells might lead to insufficient potassium recycling to the endolymph and subsequent degeneration of the organ of Corti; however, it is not known whether the observed degree of fibrocyte degeneration is extensive enough to cause this secondary pathology.
In a genetic approach to understanding presbycusis, a locus associated with the B6 hearing loss phenotype was mapped to Chromosome 10 and given the name ‘age-related hearing loss’, symbol ahl (Erway et al., 1993, Johnson et al., 1997, Johnson et al., 2000). The modifier of deaf waddler gene (mdfw), which modifies the hearing loss phenotype in mice with mutations of the Atp2b2 gene (a member of the plasma membrane Ca2+ pump family of genes) may be allelic with ahl (Zheng and Johnson, 2001). The ahl locus also has been identified as a contributor to susceptibility to acoustic trauma (Davis et al., 2001, Jimenez et al., 2001). Recent evidence indicates that inbred strain-specific alleles of the cadherin 23 gene (Cdh23) are responsible for the hearing loss effects attributed to the ahl/mdfw locus (Noben-Trauth et al., 2003).
Quite unlike the B6 animals, CAST/Ei mice (henceforth CAST), which are inbred from wild-derived Mus musculus castaneus, still have good hearing at 15 months of age (Zheng et al., 1999). It was by crossing these mice with B6 mice that the ahl locus was mapped and its effect evaluated up to 18 month of age (Johnson et al., 1997). It is assumed that CAST mice are homozygous for a dominant, wild-type allele at the ahl locus (+ahl) that confers resistance to hearing loss.
B6.CAST-+ahl is an inbred strain of congenic mice that is identical to the B6 strain except for a small region of Chromosome 10 containing the ahl locus from the CAST strain (Johnson et al., 1997). This congenic strain was still under development at the time of the 1997 publication in which it was originally described. Since then it has been backcrossed twice more to B6 mice and then inbred for many additional generations. The 1997 paper reported results for N7 or N8 generation backcross mice that were either homozygous for B6 alleles or heterozygous for B6 and CAST alleles at the ahl locus. The current study reports on the completed B6.CAST-+Ahl congenic strain after 10 backcross generations (N10) and extensive inbreeding so that all loci are now homozygous. We compare auditory brainstem response (ABR) thresholds and cochlear pathology of mice from this congenic strain with those of mice from the parental B6 and CAST inbred strains sampled at different ages. These comparisons provide a means to evaluate the isolated genetic effect of the ahl locus on hearing loss in these mice.
Section snippets
Mice
Three strains of mice from The Jackson Laboratory (Bar Harbor, ME, USA) were compared for their age-related hearing loss and cochlear degeneration pattern. The first group (n=32) consisted of mice of the common B6 inbred strain, which are homozygous for the recessive Chromosome 10 ahl susceptibility allele (ahl/ahl). The second group (n=19) consisted of mice of the CAST strain, which are homozygous for the resistance allele (+ahl/+ahl). The third group (n=33) consisted of inbred congenic mice,
Genetic definition of the B6.CAST-+ahl congenic region
The B6.CAST-+ahl congenic strain was still under development when it was originally described (Johnson et al., 1997). To better define the extent of the CAST/Ei-derived region in the now completed congenic strain, we typed 15 genetic markers along the length of Chromosome 10 (Table 1). The genetic map positions for these markers as assigned by the Mouse Genome Database (MGD) indicate that the congenic region extends for a genetic distance of about 9 cM. The DNA sequence positions in megabases
Discussion
These are exciting times in the study of presbycusis, as the components and interactions between the different contributors to this condition are being identified (Fischel-Ghodsian et al., 1997, Seidman et al., 2002, Fransen et al., 2003). Since researchers began using mice as experimental animals and creating inbred strains, many genetic loci that affect inner ear structure and function have been mapped. With the advent of molecular biological techniques for identifying the genes associated
Acknowledgements
The authors wish to thank Tim Truong, Kristin Meuller, Anna Vigran, Jenny Hong, Jennifer Lee, M.D., and Heping Yu for their technical contributions. This work was supported by NIH NIDCD DC RO-1 003395 (to E.M.K.), the Medical Research Service of the Department of Veterans Affairs, NIDCD contract DC 62108 (to K.R.J.) and TJL institutional shared services supported by National Cancer Institute grant CA34196.
References (28)
- et al.
Genetic basis for susceptibility to noise-induced hearing loss in mice
Hear. Res.
(2001) - et al.
Cochlear spiral ganglion cell degeneration in wild-caught mice as a function of age
Hear. Res.
(1996) - et al.
Genetics of age-related hearing loss in mice: I. Inbred and F1 hybrid strains
Hear. Res.
(1993) - et al.
Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations
Hear. Res.
(1997) - et al.
Age-related hearing impairment (ARHI): environmental risk factors and genetic prospects
Exp. Gerontol.
(2003) - et al.
A major gene affecting age-related hearing loss in C57BL/6J mice
Hear. Res.
(1997) - et al.
A major gene affecting age-related hearing loss is common to at least ten inbred strains of mice
Genomics
(2000) - et al.
ahl2, a second locus affecting age-related hearing loss in mice
Genomics
(2002) - et al.
The functional age of hearing loss in a mouse model of presbycusis. I. Behavioral assessments
Hear. Res.
(2003) - et al.
Molecular mechanisms of age-related hearing loss
Ageing Res. Rev.
(2002)
Pattern of degeneration of the spiral ganglion cell and its processes in the C57BL/6J mouse
Hear. Res.
Aging and presbycusis: effects on 2-deoxy-D-glucose uptake in the mouse auditory brain stem in quiet
Exp. Neurol.
Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses
Hear. Res.
Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice
Hear. Res.
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2022, NeuroscienceCitation Excerpt :Mutations in the gene encoding Cdh23 affect tip link formation and stability, which is necessary for normal hair cell mechanotransduction (Alagramam et al., 2011). Because the Cdh23753A mutation is known to promote early onset of ARHL in C57BL/6J mice (Keithley et al., 2004; Someya et al., 2007; Someya et al., 2009), it is possible that hair cells in mice carrying the Cdh23753A mutation are more susceptible to cytosolic mtDNA, thereby limiting the general implication of our findings. However, the C57BL/6J strain displays the classic pattern of ARHL (Zheng et al., 1999; Someya and Prolla, 2010).