Biology Reference
In-Depth Information
onset hearing loss in humans suggests that this transcription factor may also
have a role in hair cell maintenance.
2.4 Abnormal Endolymph Homeostasis
A number of the genes involved in deafness in humans appear likely to
have a role in maintaining the homeostasis of the endolymph of the
cochlear duct (eg Steel 1999 Table 8.4), which emphasizes the importance
of the properties of endolymph in allowing hair cells to function normally.
Endolymph has an unusual ionic composition, with high potassium and low
sodium levels, and is maintained at a high positive resting potential (endo-
cochlear potential, EP) of around 100 mV in a mouse. The high positive
potential provides a large potential difference across the top of the hair cell,
from the positive endolymph to the negative interior of the hair cell, which
presumably aids cation flow through the transduction channels. The pre-
dominance of potassium in the endolymph means that a large proportion
of the transduction current that passes through the transduction channel is
potassium rather than sodium, and a large influx of sodium would proba-
bly have a deleterious effect on the cell. The high-potassium, low-sodium
levels are present at birth, but the EP develops postnatally, from around 10
to 20 mV at six days to adult levels by around two weeks of age (Steel and
Barkway 1989). The stria vascularis on the lateral wall of the cochlear duct
is primarily responsible for generating the EP and (presumably) the ionic
composition of endolymph. The stria is believed to generate EP by elec-
trogenic pumping of potassium into the endolymph.
The stria vascularis has an abundant supply of blood vessels, but the
potassium pumped into the cochlear duct is not immediately derived from
blood (Marcus 1986; Salt et al. 1987). There are several lines of circum-
stantial evidence that potassium may be recycled around the cochlear duct
(Fig. 8.4). This was first proposed after careful ultrastructural study revealed
an extensive network of gap junctions that link supporting cells of the organ
of Corti together, and fibrocytes of the spiral ligament and spiral limbus to
their neighbours (Kikuchi et al. 1995; Spicer and Schulte 1996). Connexin
molecules form a core component of these gap junctions, and mutations
in several gap-junction genes expressed in these tissues cause deafness in
humans. The most common form of recessive human nonsyndromic deaf-
ness is due to mutations in the
GJB2
gene, encoding connexin 26 (Griffith
and Friedman, Chapter 6), and this gene is widely expressed in gap junc-
tions in the cochlea. Unfortunately, knockout of this gene causes very early
embryonic lethality in mice because of an essential role in mouse placen-
tal development (Gabriel et al. 1998), unrelated to its function in the ear.
No doubt conditional mutants will be constructed to allow investigation of
its role in cochlear function.
The human and mouse mutations in genes expressed along the puta-
tive potassium recycling route allow piecing together of some of the steps
