Whirler Mutant Hair Cells Have Less Severe Pathology than Shaker 2 or Double Mutants

Abstract

MYOSIN XV is a motor protein that interacts with the PDZ domain-containing protein WHIRLIN and transports WHIRLIN to the tips of the stereocilia. Shaker 2 (sh2) mice have a mutation in the motor domain of MYOSIN XV and exhibit congenital deafness and circling behavior, probably because of abnormally short stereocilia. Whirler (wi) mice have a similar phenotype caused by a deletion in the third PDZ domain of WHIRLIN. We compared the morphology of Whrn wi/wi and Myo15 sh2/sh2 sensory hair cells and found that Myo15 sh2/sh2 have more frequent pathology at the base of inner hair cells than Whrn wi/wi, and shorter outer hair cell stereocilia. Considering the functional and morphologic similarities in the phenotypes caused by mutations in Myo15 and Whrn, and the physical interaction between their encoded proteins, we used a genetic approach to test for functional overlap. Double heterozygotes (Myo15 sh2/+, Whrn wi/+) have normal hearing and no increase in hearing loss compared to normal littermates. Single and double mutants (Myo15 sh2/sh2, Whrn wi/wi) exhibit abnormal persistence of kinocilia and microvilli, and develop abnormal cytoskeletal architecture. Double mutants are also similar to the single mutants in viability, circling behavior, and lack of a Preyer reflex. The morphology of cochlear hair cell stereocilia in double mutants reflects a dominance of the more severe Myo15 sh2/sh2 phenotype over the Whrn wi/wi phenotype. This suggests that MYOSIN XV may interact with other proteins besides WHIRLIN that are important for hair cell maturation.