Mariner is defective in myosin VIIA: a zebrafish model for human hereditary deafness

Abstract

The zebrafish (Danio rerio) possesses two mechanosensory organs believed to be homologous to each other: the inner ear, which is responsible for the senses of audition and equilibrium, and the lateral line organ, which is involved in the detection of water movements. Eight zebrafish circler or auditory/vestibular mutants appear to have defects specific to sensory hair cell function. The circler genes may therefore encode components of the mechanotransduction apparatus and/or be the orthologous counterparts of the genes underlying human hereditary deafness. In this report, we show that the phenotype of the circler mutant, mariner, is due to mutations in the gene encoding Myosin VIIA, an unconventional myosin which is expressed in sensory hair cells and is responsible for various types of hearing disorder in humans, namely Usher 1B syndrome, DFNB2 and DFNA11. Our analysis of the fine structure of hair bundles in the mariner mutants suggests that a missense mutation within the C-terminal FERM domain of the tail of Myosin VIIA has the potential to dissociate the two different functions of the protein in hair bundle integrity and apical endocytosis. Notably, mariner sensory hair cells display morphological and functional defects that are similar to those present in mouse shaker-1 hair cells which are defective in Myosin VIIA. Thus, this study demonstrates the striking conservation of the function of Myosin VIIA throughout vertebrate evolution and establishes mariner as the first fish model for human hereditary deafness.

Auditory Input to CNS Is Acquired Coincidentally with Development of Inner Ear after Formation of Functional Afferent Pathway in Zebrafish

“…2, 4) including the appearance of the macular HCs and the hair bundles (Fig. 2) (Haddon and Lewis, 1996;Riley et al, 1997;Haddon et al, 1998;Omori and Malicki, 2006), (2) the early expression of mechanotransduction-related molecules (Ernest et al, 2000;Seiler et al, 2004Seiler et al, , 2005Söllner et al, 2004), and (3) the early formation of presynaptic molecules responsible for synaptic transmission to the VIIIth nerve afferents (Fig. 2) Obholzer et al, 2008).…”

Development of the zebrafish inner ear

“…Later, pax2.1 expression is restricted to hair cells alone . At this time, the first maturing hair cells begin to express myoVIIA, a component of stereociliary bundles (Ernest et al, 2000, and Markers of early crista development include members of the bone morphogenetic protein (BMP) family of signaling molecules. In all the major model vertebrate organisms (mouse, chick, Xenopus, and zebrafish), BMP4 mRNA expression at the rostral and caudal ends of the otic vesicle prefigures the developing rostral (superior) and caudal cristae (Hemmati-Brivanlou and Thomsen, 1995;Wu and Oh, 1996;Morsli et al, 1998;Mowbray et al, 2001; Fig.…”

Usher Syndrome: Genes, Proteins, Models, Molecular Mechanisms, and Therapies

“…Zebrafish models for several USH genes have also been reported, including mariner (myo7a), ush1c, sputnik (cdh23), and orbiter (pcdh15) (Phillips et al, 2011;Nicolson et al, 1998;Ernest et al, 2000;Sollner et al, 2004;Seiler et al, 2005). Defects in hearing, balance, and vision are manifested during the early life in two ush1c mutants.…”