Biology Reference
In-Depth Information
Two of these tectorial membrane genes are known to be involved in
human hereditary deafness; they are
COL11A2
and
TECTA
.
TECTA
is
mutated in some forms of both dominant and recessive nonsyndromic
deafness (DFNA8/12 and DFNB21), while
COL11A2
underlies the
nonsyndromic DFNA13 as well as syndromic deafness in Stickler/OSMED
syndrome (Griffith and Friedman, Chapter 6). It seems likely that tectorial
membrane abnormalities underlie the hearing impairment seen in these
forms of human deafness. People with mutations of the thyroid hormone
receptor
THRB
show resistance to thyroid hormone and often have asso-
ciated hearing impairment (Brucker-Davis et al. 1996; Refetoff et al. 1967).
It is not clear whether these people are hearing-impaired because of a tec-
torial membrane defect, or because of some other cochlear defect resulting
from delayed development.
2.6 Neural Defects
There is an increasing number of mouse mutants reported to have specific
defects in the peripheral or central auditory pathways (Tables 8.6 and 8.7).
One group of molecules, the neurotrophins and their receptors, appears to
be essential for the survival of inner ear neurons during development. Both
cochlear and vestibular afferent neurons arise from cells that delaminate
from the early otic vesicle, migrate from the epithelium to form the
cochleovestibular ganglion, extending dendrites back towards sensory hair
cells in the inner ear and axons that connect with the central auditory and
vestibular nuclei. Mice with knockouts of the brain-derived neurotrophic
factor gene (
Bdnf
), or its receptor (
Ntrk2
), have no surviving afferent
innervation of the cristae of the semicircular canals and a much reduced
afferent supply to the maculae and to cochlear outer hair cells. In contrast,
in mice with the neurotrophin-3 gene (
Ntf3
) or the corresponding receptor
gene (
Ntrk3
) disrupted, the afferent innervation of the cochlea is severely
reduced and there is minor loss of vestibular neurons. In mice that have
both receptors (
Ntrk2
and
Ntrk3
) or both neurotrophins (
Bdnf
and
Ntrk3
)
inactivated, there is a complete loss of afferent innervation to the inner ear.
The effects of these mutations have been reviewed in some detail recently
(Fritzsch et al. 1997b, 1999b and Table 8.6 for references).
Other mutations can lead to abnormal development of the inner ear
ganglia. Mutations in
Pou4f1
or
Ap2
lead to reduced or abnormal coch-
leovestibular ganglia (McEvilly et al. 1996; Zhang et al. 1996; Schorle et al.
1996), and knock-out of the neurogenin1 gene,
ngn1
, causes a complete
absence of all afferent, efferent and autonomic innervation of the inner ear
(Ma et al. 1998; Fritzsch et al. 1999a).
Efferent fibres arise from the neural tube in the hindbrain region, and
the autonomic innervation of the inner ear originates in the superior cer-
vical ganglion, a neural crest derivative (Fritzsch et al. 1997b). There are
several mutants that affect the development of the efferent system. The
