Mice as Models for Human Hereditary Deafness - Genetics of Auditory Disorders - page 258

The inner ear develops from a thickening of the surface ectoderm at the
side of the developing head, called the otic placode. This placode invaginates
into a pit that closes off from the surface to form the otic vesicle or otocyst,
lying just lateral to the neural tube. At first an ovoid shape, this otocyst
begins to develop into the characteristic shape of the mature inner ear (Fig.
8.2). The endolymphatic duct is the first structure to protrude, from the dor-
somedial region of the otocyst. Several mutants, such as kreisler and the Fgf3
and Hoxa1 knockout mutants, fail to form a normal endolymphatic duct, and
subsequent development of the inner ear is severely abnormal. Much of the
dorsal region of the otic vesicle forms the vestibular part of the ear, while the
ventral tip extends and coils round to form the cochlea. Semicircular canals
form from flattened semicircular pouches extending from the dorsal region
of the otic vesicle. The central regions of these pouches meet in the middle
and the cells there move away to leave an open rim around the edge, the
semicircular canal (Martin and Swanson 1993). The lateral canal is the last
to form, which might explain why it is the only canal to be affected, or is the
most commonly affected canal, in some mouse mutants as well as in humans.
The perilymphatic compartments form around the shape of the otic vesicle,
by the resorption of mesenchymal cells to leave fluid-filled channels, and the
bony labyrinth forms around this template by condensation of mesenchyme
to form cartilage, followed by bone deposition.
What is it that controls the development of the complex form of the
labyrinth? It has long been thought that surrounding tissues, particularly
the neural tube, have a role in patterning the otic vesicle, helping to
determine the fate of each part (Deol 1966a; Torres and Giraldez 1998).
Recent observations that mutation of some genes that are not normally
expressed in the otic vesicle can still lead to severe inner ear malformations
provides striking evidence that this is indeed the case. An example of this
is the Hoxa1 gene, which is expressed in the adjacent neural tube, but not
in the otic vesicle: knockout of this gene leads to severe inner ear malfor-
mation, presumably by a failure of the neural tube in the mutant to provide
the correct inductive signals to pattern the otic vesicle (Chisaka et al.
1992; Lufkin et al. 1991). Fekete (1996) has proposed a model to explain
how the surrounding tissues might influence the creation of compartments
within the otocyst. These compartments are marked by expression of
various genes in restricted regions of the otic epithelium. Of course,
mutations in the genes that are expressed in the otocyst can also lead to
abnormal inner ear morphogenesis. Several genes that are implicated in
morphogenetic defects of the inner ear are expressed in the otic epithelium
in positions that correlate reasonably well with the defect seen. For
example, Pax2 is expressed in the ventral otic vesicle, and mutation of the
gene leads to absence of the cochlea (Favor et al. 1996; Torres et al. 1996),
while Hmx3 is expressed in the dorsal otic vesicle, and knockout of this gene
leads to gross malformation of the vestibule (Hadrys et al. 1998; Wang
et al. 1998).