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region of predicted coiled-coil followed by a tandem repeat of MyTH4
(myosin tail homology 4)/FERM domains separated by an SH3 (src
homology 3) domain (Hasson, 1999) (Figure 2.1) Its expression is generally
restricted to specialized cell types that extend actin-filled projections such as
the retinal pigment epithelium of the eye, the sensory hair cells of the ear and
the intestinal epithelium, to name a few (Hasson et al., 1995). Mutations in
M7a result in Usher syndrome type 1B in humans, one of a collection of Usher
syndrome subtypes that are characterized by deafness and late onset retinitis
pigmentosa (Petit, 2001). Mice and zebrafish lacking M7a are deaf but do not
exhibit any overt visual defects. Detailed analyses of mouse M7a revealed that
it is expressed in the inner and outer hair cells of the cochlea where it is both
found in the cytoplasm as well as in the actin-rich stereocilia (SC) (Hasson et
al., 1997). M7a appears to be concentrated within the SC at the sites of lateral
links between adjacent SC. These links are believed to be formed by at least
two different types of cadherin, cadherin-23 and protocadherin-15
(Alagramam et al., 2001; Di Palma et al., 2001). Careful phenotypic analysis
of the mouse M7a mutant, shaker-1 (sh1), reveals that their cochlear hair cells
do extend SC but instead of being tightly organized together in a bundle they
are splayed apart (Self et al., 1998). These findings suggested that M7a plays a
role in anchoring receptors involved in forming the SC-SC links to the
underlying polarized actin bundles.
Two independent lines of investigation provide support for this hypothesis.
First, vezatin, a novel protein that binds to the C-terminal FERM domain of
M7a is present at cell-cell junctions and it can recruit the tail of M7a to these
regions of the cell (Ku¨ ssel-Andermann et al., 2000). Vezatin, in turn, is
associated with the cadherin-catenin complex (Ku
¨
ssel-Andermann et al., 2000).
Secondly, a systematic effort to identify the genes mutated in the different
subtypes of Usher syndrome type 1 that share the same gross phenotype has
resulted in the identification of harmonin, a PDZ domain-containing protein
that is mutant in Usher syndrome type 1C, as a M7a binding partner (Boe
¨
da et
al., 2002). The C-terminal FERM domain of M7a interacts with the N-terminal
PDZ domain of harmonin. Interestingly, harmonin is also capable of binding
actin via its C-terminus and the second N-terminal PDZ binding domain
interacts with the cytoplasmic tail of cadherin-23. Mutations in cadherin-23
result in Usher syndrome type 1D in humans and the waltzer deafness mutation
in mice (Bolz et al., 2001; Di Palma et al., 2001). As expected, the SC from the
cochlear hairs cells of waltzer mice appear splayed apart in much the same
manner as observed for those in the sh1 mice. Together, these results provide
strong support for the model in whichM7a plays a key role in anchoring SC-SC
links to the actin cytoskeleton and is essential for maintaining the integrity of
the hair bundle in the sensory cells of the ear.
Dictyostelium express a single M7, DdM7 (Titus, 1999), a surprising finding
when one considers the fact that these cells do not extend any stable, highly
