Biomedical Engineering Reference
In-Depth Information
2003
). Cochlea explants cultured in the presence of Sfrp1, Frzb (Sfrp3), or
WIF1 displayed disrupted bundle orientation (
Dabdoub & Kelley, 2005;
Qian et al., 2007
). Moreover, at least in the case of Frzb, the effects
could be partially rescued by increasing the concentration of Wnt5a,
indicating that Wnt signaling is disrupted by Frzb. Similarly, application
of sodium chlorate, which disrupts sulfation of polysaccharides, and
therefore disrupts HSPGs, which have a high affinity for Wnt proteins
(
Baeg, Selva, Goodman, Dasgupta, & Perrimon, 2004; Bradley & Brown,
1990
), also disrupted outer hair cell orientation
in vitro
(
Dabdoub &
Kelley, 2005
). Taken together, these results support the idea that
endogenous Wnts probably play a role in cochlear PCP; however,
whether a gradient of any Wnt is actually instructive for bundle
orientation has not yet been demonstrated.
Interestingly, several Wnt antagonists are expressed endogenously in the
cochlea. In particular,
Frzb
is expressed in a counter gradient to
Wnt5a
(
Qian
et al., 2007
). Since expression of Wnt antagonists has been shown to play a
role in refining and/or amplifying Wnt gradients (
Dabdoub & Kelley, 2005;
Kawano & Kypta, 2003; Leimeister, Bach, & Gessler, 1998
), these results are
consistent with a role for a Wnt gradient in cochlear PCP. Overall, these
results strongly support a role for Wnt signaling in the generation of
inner ear PCP, at least in the cochlea. However, the lack of a mouse
mutant with a strong inner ear PCP phenotype is clearly a crucial
requirement to confirm this hypothesis. Unfortunately, because of
functional redundancy, multiple
Wnts
may need to be deleted to achieve
this goal, but with the advent of tissue-specific deletion techniques, the
necessary mouse models may not be too far off.
3.3. Asymmetric protein localization
One of the more insightful discoveries regarding the cellular mechanisms un-
derlying PCP was the demonstration of asymmetric protein localization for
several of the core genes in
Drosophila
(
Jenny & Mlodzik, 2006; Strutt,
Johnson, Cooper, & Bray, 2002; Uemura & Shimada, 2003
). Within the
developing fly wing, fz and disheveled become localized to the distal
portion of each cell, while vg and prickle (pk) become localized to the
proximal region of each cell. Flamingo colocalizes on both the distal and
the proximal regions of each cell but is excluded from cellular membranes
oriented parallel with the axis of extension. While similarly intriguing
localization of PCP proteins in mammalian tissues has proved challenging
