Human Molecular Genetics Advance Access originally published online on December 8, 2004
Human Molecular Genetics 2005 14(3):391-400; doi:10.1093/hmg/ddi035
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Human Molecular Genetics, Vol. 14, No. 3 © Oxford University Press 2005; all rights reserved
Mutant analysis reveals whirlin as a dynamic organizer in the growing hair cell stereocilium
1MRC Mammalian Genetics Unit, Harwell OX11 ORD, UK and 2Department of Gene Regulation, Niigata Graduate School of Medicine, Niigata, Japan
* To whom correspondence should be addressed. Tel: +44 1235824541; Fax: +44 1235824542; Email: s.brown{at}har.mrc.ac.uk
Received October 18, 2004; Accepted November 29, 2004
Little is known of the molecular processes that lead to the growth of stereocilia on the surface of hair cells in the inner ear. The PDZ protein whirlin is known, by virtue of the whirler mutation, to be involved in the process of stereocilia elongation and actin polymerization in the sensory hair cells of mammals. We have investigated the function of whirlin and its putative interacting partner, myosin XVa, in the stereocilium using relevant mice mutants. We raised an antibody that detects the short isoform of the whirlin protein which has been demonstrated to rescue the stereocilia growth defect in the whirler mutant. We show that whirlin localizes at the tips of stereocilia. Expression of whirlin is dynamic during stereocilia growth, demonstrating an ordered appearance and fade-out across the stereocilia rows and revealing a novel molecular gradation of process traversing the stereocilia bundle. Fade-out of whirlin in inner hair cells precedes that of outer hair cells, consistent with the earlier maturation of inner hair cell stereocilia. In myosin XVa mutants in which stereocilia are shortened, whirlin expression in the stereocilia tips is stalled and fade-out is accelerated. In whirlin mutants, myosin XVa is still expressed in stereocilia, but its appearance at the stereocilia tip is delayed. The data indicate that whirlin expression is a critical and dynamic organizer for stereocilia elongation and actin polymerization.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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