Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly

Delprat, Benjamin; Michel, Vincent; Goodyear, Richard J.; Yamasaki, Yasuhiro; Michalski, Nicolas; El-Amraoui, Aziz; Perfettini, Isabelle; Legrain, Pierre; Richardson, Guy P.; Hardelin, Jean‐Pierre; Petit, Christine

doi:10.1093/hmg/ddi036

Cited by 168 publications

(194 citation statements)

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“…However, recent work has established that whirlin, a PSD-95͞SAP90 Discs-large ZO-1 homologous (PDZ) protein, localizes to the stereocilia tips and, by virtue of mutations in the whirlin gene, has been shown to play an important role in stereocilia development (7). Myosin XVa interacts with whirlin and is responsible for localizing whirlin at the stereocilia tip (8,9). We have recently shown that whirlin expression is dynamic during stereocilia growth, further underlining its key role in stereocilia development (10).…”

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confidence: 99%

Whirlin complexes with p55 at the stereocilia tip during hair cell development

Mburu

Kikkawa

Townsend

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Hearing in mammals depends upon the proper development of actin-filled stereocilia at the hair cell surface in the inner ear. Whirlin, a PDZ domain-containing protein, is expressed at stereocilia tips and, by virtue of mutations in the whirlin gene, is known to play a key role in stereocilia development. We show that whirlin interacts with the membrane-associated guanylate kinase (MAGUK) protein, erythrocyte protein p55 (p55). p55 is expressed in outer hair cells in long stereocilia that make up the stereocilia bundle as well as surrounding shorter stereocilia structures. p55 interacts with protein 4.1R in erythrocytes, and we find that 4.1R is also expressed in stereocilia structures with an identical pattern to p55. Mutations in the whirlin gene (whirler) and in the myosin XVa gene (shaker2) affect stereocilia development and lead to early ablation of p55 and 4.1R labeling of stereocilia. The related MAGUK protein Ca 2؉ -calmodulin serine kinase (CASK) is also expressed in stereocilia in both outer and inner hair cells, where it is confined to the stereocilia bundle. CASK interacts with protein 4.1N in neuronal tissue, and we find that 4.1N is expressed in stereocilia with an identical pattern to CASK. Unlike p55, CASK labeling shows little diminution of labeling in the whirler mutant and is unaffected in the shaker2 mutant. Similarly, expression of 4.1N in stereocilia is unaltered in whirler and shaker2 mutants. p55 and protein 4.1R form complexes critical for actin cytoskeletal assembly in erythrocytes, and the interaction of whirlin with p55 indicates it plays a similar role in hair cell stereocilia. mutant analysis ͉ stereocilia development A ctin cytoskeleton remodeling is fundamental to a variety of cellular processes, including morphological alterations at the cell surface. In the mammalian inner ear, hair cells develop highly organized bundles of actin-filled stereocilia whose most prominent feature is an extraordinary staircase arrangement. The anatomical process of stereocilia development from microvilli on the surface of hair cells in the vicinity of the kinocilium has been well described both in vivo and in organotypic culture (1-5). At around embryonic day (E)17.5 in mice, microvilli begin to elongate. As stereocilia thicken and continue to elongate, the staircase pattern emerges from around postnatal day (P)1 in mice, with morphological development complete around P5-7. Stereocilia in adjacent rows are connected by tip links that attach the tips of shorter stereocilia to the sides of neighboring taller stereocilia. Tip-link attachment sites are thought to harbor mechanotransduction channels, such that sound stimulation and stereocilia deflection lead to channel opening, cation influx, hair cell depolarization, and auditory transduction (6).Until recently, the critical molecules for development of the stereocilia bundle were unknown. However, recent work has established that whirlin, a PSD-95͞SAP90 Discs-large ZO-1 homologous (PDZ) protein, localizes to the stereocilia tips and, by virtue of mutat...

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confidence: 99%

Whirlin complexes with p55 at the stereocilia tip during hair cell development

Mburu

Kikkawa

Townsend

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Are there other cargos transported by myosin XV? Delprat et al (2005) proposed that whirlin interacts with a transmembrane protein, NGL-1, isolated from a P2-P6 mouse inner ear cDNA library. In light of similarities between the unconventional myosins XV and VIIa, the PDZ domain proteins whirlin and harmonin, and the transmembrane proteins NGL-1 and cadherin 23, these proteins may form two similar complexes required for stereocilia morphogenesis.…”

Section: Genes With Genotype Effectsmentioning

confidence: 99%

“…Myosin XV is normally located at the tips of stereocilia and within the actin-rich cuticular plate that anchors the bases of the stereocilia (Liang et al 1999;Belyantseva et al 2003). Myosin XV was recently shown to be essential in transporting whirlin to the tips of stereocilia (Belyantseva et al 2005;Delprat et al 2005;Kikkawa et al 2005). Defective myosin XV proteins in sh2 mice disrupt relevant structural interactions and/or biochemical pathways associated with this transport system and lead to stereocilia malformation.…”

Section: Introductionmentioning

confidence: 99%

Age-Related Changes in Cochlear Gene Expression In Normal and Shaker 2 Mice

Gong

Károlyi

MacDonald

et al. 2006

JARO

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The vertebrate cochlea is a complex organ optimized for sound transduction. Auditory hair cells, with their precisely arranged stereocilia bundles, transduce sound waves to electrical signals that are transmitted to the brain. Mutations in the unconventional myosin XV cause deafness in both human DFNB3 families and in shaker 2 (sh2) mice as a result of defects in stereocilia. In these mutant mice, hair cells have relatively normal spatial organization of stereocilia bundles but lack the graded, stair-step organization. We used sh2 mice as an experimental model to investigate the molecular consequences of the sh2 mutation in the Myo15 gene. Gene expression profiling with Affymetrix GeneChips in deaf homozygous (sh2/sh2) mice at 3 weeks and 3 months of age, and in age-matched, normal-hearing heterozygotes (+/sh2) identified only a few genes whose expression was affected by genotype, but a large number with age-associated changes in expression in both normal mice and sh2/sh2 homozygotes. Microarray data analyzed using Robust Multiarray Average identified Aim1, Dbi, and Tm4sf3 as genes with increased expression in sh2/sh2 homozygotes. These increases were confirmed by quantitative reverse transcription-polymerase chain reaction. Genes exhibiting altered expression with age encoded collagens and proteins involved in collagen maturation, extracellular matrix, and bone mineralization.These results identified potential cellular pathways associated with myosin XV defects, and age-associated molecular events that are likely to be involved in maturation of the cochlea and auditory function.

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“…Class III myosins shape the auditory hair bundles by limiting microvilli and stereocilia growth myosin XVa, is located at the tips of the stereocilia and forms a complex with the PDZ domain-containing protein whirlin and the actin regulatory protein Eps8, whose disruption causes stereocilia to be abnormally short at postnatal stages (Probst et al, 1998;Delprat et al, 2005;Manor et al, 2011). Myosin VIIa, defects of which cause Usher syndrome type I (USH1; Weil et al, 1995), forms a complex with other USH1 proteins harmonin,and Sans), which is required for the cohesiveness of the growing hair bundle (Petit and Richardson, 2009).…”

Section: Introductionmentioning

confidence: 99%