Abstract
The vertebrate-restricted carcinoembryonic antigen gene family evolves extremely rapidly. Among their widely expressed members, the mammal-specific, secreted CEACAM16 is exceptionally well conserved and specifically expressed in the inner ear. To elucidate a potential auditory function, we inactivated murine Ceacam16 by homologous recombination. In young Ceacam16(-/-) mice the hearing threshold for frequencies below 10 kHz and above 22 kHz was raised. This hearing impairment progressed with age. A similar phenotype is observed in hearing-impaired members of Family 1070 with non-syndromic autosomal dominant hearing loss (DFNA4) who carry a missense mutation in CEACAM16. CEACAM16 was found in interdental and Deiters cells and was deposited in the tectorial membrane of the cochlea between postnatal days 12 and 15, when hearing starts in mice. In cochlear sections of Ceacam16(-/-) mice tectorial membranes were significantly more often stretched out as compared with wild-type mice where they were mostly contracted and detached from the outer hair cells. Homotypic cell sorting observed after ectopic cell surface expression of the carboxyl-terminal immunoglobulin variable-like N2 domain of CEACAM16 indicated that CEACAM16 can interact in trans. Furthermore, Western blot analyses of CEACAM16 under reducing and non-reducing conditions demonstrated oligomerization via unpaired cysteines. Taken together, CEACAM16 can probably form higher order structures with other tectorial membrane proteins such as α-tectorin and β-tectorin and influences the physical properties of the tectorial membrane. Evolution of CEACAM16 might have been an important step for the specialization of the mammalian cochlea, allowing hearing over an extended frequency range.
Highlights
Genes evolved in mammals for specialization of hearing
A similar phenotype is observed in hearingimpaired members of Family 1070 with non-syndromic autosomal dominant hearing loss (DFNA4) who carry a missense mutation in CEACAM16
Homotypic cell sorting observed after ectopic cell surface expression of the carboxyl-terminal immunoglobulin variable-like N2 domain of CEACAM16 indicated that CEACAM16 can interact in trans
Summary
CEACAM16 has evolved in mammals to broaden the auditory frequency range. Significance: Mutation of CEACAM16 is responsible for human autosomal dominant hearing loss (DFNA4). The vertebrate-restricted carcinoembryonic antigen gene family evolves extremely rapidly Among their widely expressed members, the mammal-specific, secreted CEACAM16 is exceptionally well conserved and expressed in the inner ear. A similar phenotype is observed in hearingimpaired members of Family 1070 with non-syndromic autosomal dominant hearing loss (DFNA4) who carry a missense mutation in CEACAM16. The pathogens can gain additional benefit by down-regulation of anti-pathogen immune responses through engagement of CEACAM1 on epithelial and immune cells [8, 10, 11] This dual level assault has led to the development of very similar decoy receptors during evolution as a countermeasure by the host [1, 12, 13]. As a basis for functional analyses of this mammal-specific, highly conserved member of the CEA family, we searched expressed sequence tag (EST) databases for CEACAM16 clones. Loss of CEACAM16 resulted in an increased hearing threshold mainly for frequencies below 10 kHz and impaired amplification above threshold possibly caused by disruption of the striated sheet of the TM with a concomitant change of its elasticity
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