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Updated: Jul 13, 2026
Evaluation of Planar-Cell-Polarity Phenotypes in Ciliopathy Mouse Mutant Cochlea
Published on: February 21, 2016
Whirler mutant hair cells have less severe pathology than shaker 2 or double mutants
Mirna Mustapha1, Lisa A Beyer, Masahiko Izumikawa
1Department of Human Genetics, University of Michigan, 4909 Buhl Building, 1241 East Catherine Street, Ann Arbor, MI 48109-0618, USA.
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.
Insights
Mutations in MYOSIN XV and WHIRLIN cause hearing loss by affecting stereocilia development. Genetic analysis reveals MYOSIN XV plays a dominant role, suggesting interactions with other proteins crucial for hair cell maturation.
Area of Science:
- Genetics
- Cell Biology
- Otolaryngology
Background:
- MYOSIN XV (Myo15) and WHIRLIN (Whrn) are proteins essential for stereocilia development in sensory hair cells.
- Mutations in MYOSIN XV (shaker 2 mice) and WHIRLIN (whirler mice) lead to congenital deafness and abnormal stereocilia morphology.
- Both proteins interact physically, suggesting a potential functional relationship in hair cell development.
Purpose of the Study:
- To investigate the functional overlap between MYOSIN XV and WHIRLIN using a genetic approach.
- To compare the phenotypic effects of single and double mutations in Myo15 and Whrn on sensory hair cell development and function.
- To elucidate the roles of MYOSIN XV and WHIRLIN in the maturation of cochlear hair cells.
Main Methods:
- Morphological comparison of sensory hair cells from Myo15 (sh2/sh2) and Whrn (wi/wi) mutant mice.
- Generation and analysis of double heterozygote (Myo15 (sh2/+), Whrn (wi/+)) and double mutant (Myo15 (sh2/sh2), Whrn (wi/wi)) mice.
- Assessment of auditory function (hearing loss, Preyer reflex) and behavioral phenotypes (circling behavior).
Main Results:
- Myo15 (sh2/sh2) mutants showed more basal pathology in inner hair cells and shorter outer hair cell stereocilia compared to Whrn (wi/wi) mutants.
- Double heterozygotes exhibited normal hearing, indicating no significant additive effect of single mutations.
- Double mutants displayed abnormal persistence of kinocilia and microvilli, altered cytoskeletal architecture, and retained the severe phenotypes of the single mutants, with Myo15 (sh2/sh2) being dominant.
Conclusions:
- MYOSIN XV and WHIRLIN play critical roles in sensory hair cell development and stereocilia formation.
- The MYOSIN XV (sh2/sh2) mutation phenotype is dominant over the WHIRLIN (wi/wi) mutation phenotype in double mutants.
- These findings suggest that MYOSIN XV may interact with additional proteins beyond WHIRLIN that are vital for hair cell maturation and function.
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