MSM/Ms is an inbred mouse strain derived from a Japanese wild mouse, Mus musculus molossinus. In this study, we showed that MSM/Ms mice exhibit dominant resistance when crossed with susceptible FVB/N mice and subjected to the two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene (DMBA)/ 12-O-tetradecanoylphorbol-13-acetate (TPA). A series of F1 backcross mice were generated by crossing p53(+/+) or p53(+/-) F1 (FVB/N × MSM/Ms) males with FVB/N female mice. These generated 228 backcross animals, approximately half of which were p53(+/-), enabling us to search for p53-dependent skin tumor modifier genes. Highly significant linkage for papilloma multiplicity was found on chromosomes 6 and 7 and suggestive linkage was found on chromosomes 3, 5 and 12. Furthermore, in order to identify stage-dependent linkage loci we classified tumors into three categories (<2mm, 2-6mm and >6mm), and did linkage analysis. The same locus on chromosome 7 showed strong linkage in groups with <2mm or 2-6mm papillomas. No linkage was detected on chromosome 7 to papillomas >6mm, but a different locus on chromosome 4 showed strong linkage both to papillomas >6mm and to carcinomas. This locus, which maps near the Cdkn2a/p19(Arf) gene, was entirely p53-dependent, and was not seen in p53 (+/-) backcross animals. Suggestive linkage conferring susceptibility to carcinoma was also found on chromosome 5. These results clearly suggest distinct loci regulate each stage of tumorigenesis, some of which are p53-dependent.
The waltzer (v) mouse mutant harbors a mutation in Cadherin 23
(Cdh23) and is a model for Usher syndrome type 1D, which is
characterized by congenital deafness, vestibular dysfunction, and prepubertal onset of
progressive retinitis pigmentosa. In mice, functionally null Cdh23
mutations affect stereociliary morphogenesis and the polarity of both cochlear and
vestibular hair cells. In contrast, the murine Cdh23ahl
allele, which harbors a hypomorphic mutation, causes an increase in susceptibility to
age-related hearing loss in many inbred strains. We produced congenic mice by crossing
mice carrying the v niigata (Cdh23v-ngt) null
allele with mice carrying the hypomorphic Cdh23ahl allele on
the C57BL/6J background, and we then analyzed the animals’ balance and hearing phenotypes.
Although the
Cdh23v-ngt/ahl
compound heterozygous mice exhibited normal vestibular function, their hearing ability was
abnormal: the mice exhibited higher thresholds of auditory brainstem response (ABR) and
rapid age-dependent elevation of ABR thresholds compared with
Cdh23ahl/ahl
homozygous mice. We found that the stereocilia developed normally but were progressively
disrupted in
Cdh23v-ngt/ahl mice.
In hair cells, CDH23 localizes to the tip links of stereocilia, which are thought to gate
the mechanoelectrical transduction channels in hair cells. We hypothesize that the
reduction of Cdh23 gene dosage in
Cdh23v-ngt/ahl mice
leads to the degeneration of stereocilia, which consequently reduces tip link tension.
These findings indicate that CDH23 plays an important role in the maintenance of tip links
during the aging process.
Most clinical reports have suggested that patients with congenital profound hearing loss have recessive mutations in deafness genes, whereas dominant alleles are associated with progressive hearing loss (PHL). Jackson shaker (Ush1g) is a mouse model of recessive deafness that exhibits congenital profound deafness caused by the homozygous mutation of Ush1g/Sans on chromosome 11. We found that C57BL/6J-Ush1g heterozygous mice exhibited early-onset PHL (ePHL) accompanied by progressive degeneration of stereocilia in the cochlear outer hair cells. Interestingly, ePHL did not develop in mutant mice with the C3H/HeN background, thus suggesting that other genetic factors are required for ePHL development. Therefore, we performed classical genetic analyses and found that the occurrence of ePHL in Ush1g mice was associated with an interval in chromosome 10 that contains the cadherin 23 gene (Cdh23), which is also responsible for human deafness. To confirm this mutation effect, we generated C57BL/6J-Ush1g, Cdh23 double-heterozygous mice by using the CRISPR/Cas9-mediated Cdh23 knock-in method. The Cdh23 mice harbored a one-base substitution (A for G), and the homozygous A allele caused moderate hearing loss with aging. Analyses revealed the complete recovery of ePHL and stereocilia degeneration in C57BL/6J-Ush1g mice. These results clearly show that the development of ePHL requires at least two mutant alleles of the Ush1g and Cdh23 genes. Our results also suggest that because the SANS and CDH23 proteins form a complex in the stereocilia, the interaction between these proteins may play key roles in the maintenance of stereocilia and the prevention of ePHL.
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