Biomedical Engineering Reference
In-Depth Information
not required for mechanotransduction (
Hudspeth & Jacobs, 1979
), and
while they persist in most hair cells, they are actually lost in the mammalian
cochlea shortly before the onset of hearing. These results, and earlier dis-
cussed data on kinocilia movements during bundle formation, have led to
the suggestion that they play an important role in the development and ori-
entation of the stereociliary bundles.
One of the first demonstrations that developing kinocilia are important
in PCP signaling was the identification of PCP defects in ciliary mutants.
Ciliopathies refer to a range of human disease syndromes that are caused
by defects in primary cilia function. One of these syndromes, Bardet-Biedl
syndrome (BBS), is caused by mutations in several genes including
MKKS
and
BBS4
(
Forsythe & Beales, 2012
), which have been shown to localize to
the base of the cilium. Analysis of the effects of loss or inhibition of either
gene indicated convergence extension defects in zebrafish and rotated
stereociliary bundles in mice (
Ross et al., 2005; Simons et al., 2005
).
Bbs4
-null mice also displayed craniorachischisis and open eyelids,
phenotypes that are also associated with PCP defects. Further, in addition
to abnormal rotation, in
Mkks
/
cochleae, some stereociliary bundles
displayed kinocilia that were detached from the rest of the bundle. These
mice also had abnormal distortion product otoacoustic emissions
(DPOAEs) indicating defects in auditory function, possibly as a result of
abnormal stereociliary bundles. Finally,
Mkks
and
Bbs4
were shown to
interact genetically with
Vangl2
in both mice and zebrafish (
Ross et al.,
2005; Simons et al., 2005
). More recently, Vangl2 has also been shown
to interact biochemically with another BBS protein,
bbs8
, in zebrafish
(
May-Simera et al., 2010
). Consistent with this finding, knockdown of
bbs8
in combination with a mutation in
vangl2
results in cilia-based
defects in fluid flow in Kuppfer's vesicle (
May-Simera et al., 2010
). A
potential mechanism for some of these defects was recently presented in a
study that examined interactions between
Mkks
and
Cep290
, another
ciliopathy gene (
Rachel et al., 2012
). While animals that were
homozygous for either
Cep290
rd16
, the causative mutation for LCA-like
(ciliopathy) defects in mice, or an
Mkks
deletion both displayed
significant hearing loss and some degree of PCP defect, combinations of
the two mutant genes actually displayed a significant degree of rescue.
Further, examination of kinocilia indicated a significant increase in length
in
Cep290
rd16
mice, a significant shortening in
Mkks
mutants and a rescue
in some genetic combinations, suggesting that regulation of kinociliary
length is important for normal PCP and auditory function.
