The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells

Abstract

Recessive mutations in myosin 15, a class XV unconventional myosin, cause profound congenital deafness in humans and both deafness and vestibular dysfunction in mice homozygous for the shaker 2 and shaker 2(J) alleles. The shaker 2 allele is a previously described missense mutation of a highly conserved residue in the motor domain of myosin XV. The shaker 2(J) lesion, in contrast, is a 14.7 kb deletion that removes the last six exons from the 3"-terminus of the Myo15 transcript. These exons encode a FERM (F, ezrin, radixin and moesin) domain that may interact with integral membrane proteins. Despite the deletion of six exons, Myo15 mRNA transcripts and protein are present in the post-natal day 1 shaker 2(J) inner ear, which suggests that the FERM domain is critical for the development of normal hearing and balance. Myo15 transcripts are first detectable at embryonic day 13.5 in wild-type mice. Myo15 transcripts in the mouse inner ear are restricted to the sensory epithelium of the developing cristae ampularis, macula utriculi and macula sacculi of the vestibular system as well as to the developing organ of Corti. Both the shaker 2 and shaker 2(J) alleles result in abnormally short hair cell stereocilia in the cochlear and vestibular systems. This suggests that Myo15 may be important for both the structure and function of these sensory epithelia.

The role of bone morphogenetic protein 4 in inner ear development and function

“…The Jerker mouse, Ames waltzer, Shaker 1, waltzer, Shaker 2 and Snell's waltzer have mutations identified in espin, protocadherin15, myosinVIIa, cadherin23, myosin XVa and myosinVI respectively (Wang et al, 1998;Liang et al, 1999;Anderson et al, 2000;Zheng et al, 2000;Holme and Steel, 2002;Karolyi at al., 2003;Siemens et al, 2004). All of these mutant mice have disorganized stereocilia in the hair cells of the organ of Corti, but the Jerker mouse and Ames waltzer mouse also have shortened stereocilia in the vestibular tissues (Zheng et al, 2000;Raphael et al, 2001).…”

Rescue of Hearing by Gene Delivery to Inner-Ear Hair Cells Using Exosome-Associated AAV

“…[20][21][22] Because GFP-positive hair cells were also evident in vestibular sensory epithelia, suggesting vector diffusion to the vestibular system (Figure 3), we performed behavioral tests in treated (injected through the RWM with exo-AAV1-HA-Lhfpl5) and nontreated Lhfpl5 KO mice. We performed www.moleculartherapy.org an open field test, in which animals were placed in a circular arena for 5 min.…”

Inhibition of Myo6 gene expression by co-expression of a mutant of transcription factor POU4F3 (BRN-3C) in hair cells

“…Normally present on cilia and actin-rich microvilli, including the stereocilia on mammalian hair cells, unconventional myosins are required for the cohesion and structural integrity of the bundle (11,(37)(38)(39). Myosin VI, encoded by Myo6, is expressed in the inner and outer hair cells of mouse cochlea, concentrating in the actin-rich cuticular plate associated with stereociliary rootlets, pericuticular necklaces, and cytoplasm (11,15).…”