Biomedical Engineering Reference
In-Depth Information
may dictate other aspects of cellular identity with bundle orientation
determined based on as-yet-unknown facets of that identity. Second, the re-
sults also suggest fundamental differences between PCP in the auditory and
vestibular systems despite the use of the same core PCP components. This
suggestion is supported by the observation of significantly different polarity
defects in response to similar mutations. For instance, deletion of
Fz3
and
Fz6
has a minimal effect on bundle orientation in the utricle but leads to
a nearly 180
reversal in the orientation of inner hair cell bundles. While
these observations do not minimize the importance of the PCP pathway
in stereociliary bundle orientation or the validity of bundle orientation as
a read out of PCP, they do represent important considerations for the ex-
amination of other PCP mutants in terms of inner ear defects.
3.4. Novel coreceptors
As discussed, Wnt signaling plays a role in vertebrate PCP. Therefore, it is
not unexpected that some Wnt coreceptors might also influence bundle ori-
entation. In particular, the Ror kinases are a family of transmembrane recep-
tors that have been proposed to mediate the role of Wnt ligands in PCP
signaling (
Minami, Oishi, Endo, & Nishita, 2010
). Ror kinases physically
interact with Wnt5a homologs in
Caenorhabditis elegans
and
Xenopus
and
are required for cell polarization and convergence extension (
Forrester,
Dell, Perens, & Garriga, 1999; Oishi et al., 2003
).
Ror2
knockout mice
display a similar phenotype to
Wnt5a
mutants, including convergence
extension defects and misoriented cochlear hair cells (
Forrester et al.,
1999
). Recently, Wnt5a was shown to act through Ror2 to induce
Vangl2 phosphorylation, establishing a PCP activity gradient of Vangl2 in
the developing vertebrate limb. Vangl2 and Ror2 were shown to form a
Wnt-induced receptor complex resulting in the dosage-dependent
phosphorylation of Vangl2 depending on Wnt5a dosages (
Gao et al.,
2011
). Similarly, the secreted collagen triple helix repeat-containing 1
glycoprotein (Cthrc1) has been shown to stabilize Wnt, Fz, Ror2
receptor complexes, and
Cthrc1
-null mice genetically interact with
Vangl2
Lp
to cause cochlear PCP phenotypes (
Yamamoto et al., 2008
).
3.5. Cytoplasmic mediators
In addition to the core PCP cytoplasmic mediators Dvl and Pk, several novel
cytoplasmic proteins have also been shown to mediate PCP in vertebrates
and, in particular, in the inner ear. The mammalian
Scribble
(
Scrib
) gene, a
