Mice as Models for Human Hereditary Deafness - Genetics of Auditory Disorders - page 263

shaker2 mutant. In these mice, the stereocilia are all shorter than normal,
although they are arranged in the normal V-shape on top of each hair cell
(Probst et al. 1998). Again, hair cells ultimately die in both Snell's waltzer
and shaker2 mutants.
The shaker1, Snell's waltzer and shaker2 genes have all been identified
by positional cloning, and interestingly they all involve unconventional
myosin genes, Myo7a , Myo6 , and Myo15 respectively. These three myosins
obviously have important, but distinctive, roles in the development and
maintenance of stereocilia bundles on hair cells. On the basis of its distri-
bution along the cell membrane covering each stereocilium, it has been sug-
gested that myosin VIIa may play a role in cross-linking stereocilia, possibly
by transporting or anchoring the extracellular link material (Hasson et al.
1997). Myosin VI, on the other hand, might be important in anchoring the
cell membrane between adjacent stereocilia to the actin-rich cuticular plate
just below the apical surface of the hair cell; this could prevent the natural
tendency of lipid membranes in water to adopt the lowest possible surface
area, which would lead to the observed “zipping up” of these membranes
in the mutants (Self et al. 1999).
Two mutants demonstrate little or no development of sensory hair cells.
The Math1 knockout mutant shows no sign of development of hair cells
within the organ of Corti (Bermingham et al. 1999), suggesting that the gene
is essential for differentiation of these cells. It is the earliest gene known to
be involved in the cascade of gene activity that results in a differentiated
hair cell, and is thus of much interest to those working on hair cell regen-
eration. The Pou4f3 knockout mutant also shows very little differentiation
of hair cells (Erkman et al. 1996; Xiang et al. 1997), but expression studies
show that early hair cell markers like Myo7a are expressed in cells in the
position of putative hair cells, indicating that differentiation of the hair cell
phenotype does begin in these mutants (Xiang et al. 1998). Pou4f3 must
therefore act later in hair cell differentiation than Math1 .
Two genes have been shown to have a role in cell fate determination or
proliferation in the organ of Corti. Jagged2 knockout mutants have an
increased number of hair cells (Lanford et al. 1999). This gene is known to
be involved in Notch/Delta signalling, so this observation supports the pro-
posal that lateral inhibition mediated by Notch/Delta homologues plays a
role in determining whether a cell becomes a hair cell or a supporting cell.
Because supporting cells did develop in the Jagged2 mutants, this suggests
that Jagged2 is not the only Notch ligand involved in the process of decid-
ing cell fate, but that other factors must also be involved. The second gene
in this category is p27 Kip1 (Chen and Segil 1999; Löwenheim et al. 1999). In
mutants with this gene inactivated, cell proliferation continues beyond the
normal time of cell division in the organ of Corti, leading to additional cells
being formed.
The bronx waltzer mutant has a unique cochlear pathology. Most inner
hair cells and vestibular hair cells die from around 17.5 days of gestation,