Biomedical Engineering Reference
In-Depth Information
PCP phenotypes in other ciliopathy models strengthen the association of
PCP with cilia. In particular, mispositioned and abnormally rotated
stereociliary bundles are present on outer hair cells in
Mks1
mutant mice
(a mouse model for the ciliopathy Meckel-Gruber syndrome) (
Cui et al.,
2011
). Similar to
Mkks
/
, kinocilia were also abnormally localized in re-
lation to the stereociliary bundles in these mutants. Mutations in
Inversin
,a
ciliary protein that localizes to the basal body, a modified centriole anchoring
the cilium, cause nephronophthisis, which is also considered a ciliopathy-
related disease (
Lienkamp, Ganner, & Walz, 2012; Wolf & Hildebrandt,
2011
). Knockdown of
Inversin
in
Xenopus
or zebrafish leads to
convergence and extension defects, and Inversin has been shown to act as
a molecular switch between canonical and noncanonical (PCP) signaling,
by targeting cytoplasmic disheveled for degradation (
Simons et al., 2005
).
However, a role for Inversin within the inner ear has not been examined.
Alstrom syndrome is the only ciliopathy in which hearing loss is a com-
ponent of the clinical phenotype (
Marshall, Maffei, Collin, & Naggert,
2011
). Cochlear analysis of
Alms1
knockout mice, the only known causative
gene for Alstrom syndrome thus far, identified flattened and rotated
stereociliary bundles, yet no detachment of the kinocilium from the bundles
was reported (
Jagger et al., 2011
). Auditory brainstem responses and
DPOAEs were normal in juvenile mutants but did become disrupted in
older animals. Similar to other ciliopathy proteins, Alms1 localizes to basal
bodies in both hair cells and supporting cells.
Complete ablation of the kinocilium, as occurs in
Ift88
and
Kif3a
con-
ditional mutants, results in more severe cochlear PCP phenotypes (
Jones
et al., 2008; Sipe & Lu, 2011
) that include shortened cochleae, and
rotated and misshapen bundles, some of which resemble donuts with
stereocilia forming a circle on the surface of the hair cell. Both of these
proteins are crucial for intraflagellar transport (IFT), which involves the
bidirectional transport of proteins along the microtubule-based ciliary
axoneme. As the cilia lacks the ability to generate its own proteins, loss of
IFT leads to cilia agenesis. Although
Ift88
has been shown to genetically
interact with
Vangl2
mutants resulting in more extreme cochlear
phenotypes, the asymmetric distribution of both Vangl2 and Fz3 within
developing hair cells is undisturbed in
Ift88
and
Kif3a
mutants, suggesting
that the role of the kinocilium is downstream from the core PCP
molecules. However, results in other model systems suggest that cilia
mediate cell polarity via positioning of the centrosome (
Park et al., 2008;
Tissir et al., 2010
), placing cilia and basal body proteins upstream of core
