Biomedical Engineering Reference
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(
Dabdoub et al., 2003
). Consistently, treatment with Sfrp1 or Wif1 (Wnt
inhibitory factor 1), which neutralizes all endogenous Wnt proteins, also
disrupts the outer hair cell reorientation (
Dabdoub et al., 2003
). These
evidence suggest a role of Wnt7a as an instructive cue for reorientation of
sensory hair cells by regulating PCP during inner ear cochlea development.
However, to distinguish the instructive or permissive role of Wnt morpho-
gen gradient in regulating sensory hair cell orientation in the inner ear,
artificial Wnt gradient should be generated to test whether it is sufficient
to redirect the polarity of sensory hair cells (
Dabdoub & Kelley, 2005
).
In addition, it is puzzling why treatment with Wn7a conditional medium,
Sfrp1, or Wif1 has no effect on inner hair cell orientation, which indicates
a possible Wnt-independent mechanism (
Dabdoub et al., 2003
). Since sen-
sory hair cell orientation is a complicated model system to study mammalian
PCP, genetic manipulation in other systems and
in vitro
culture assay will
help us to further dissect the role of Wnt morphogen gradient in PCP,
whether the role is instructive or permissive.
Taken together, it appears that more evidence supports an instructive,
rather than permissive role of Wnt morphogen in establishing PCP in ver-
tebrates. However, there is so far no direct genetic evidence to demonstrate
the instructive model or rule out the permissive model. The mechanism
whereby Wnt gradient sets up the PCP or asymmetrically localized PCP
proteins needs to be further investigated. The findings of Wnt-regulated
Vangl2 phosphorylation may provide more insight to this issue.
3. MISSING LINK BETWEEN Wnt AND PCP
From the discovery of
Wnt1
in mouse mammary gland tumors (
Nusse
& Varmus, 1982
) and the findings of major downstream components, there
is a great advance in our understandings of canonical Wnt signal transduc-
tions in both development and disease (
Klaus & Birchmeier, 2008
). In con-
trast, while genetic studies of PCP or tissue polarity also emerged around
30 years ago (
Gubb &Garcia-Bellido, 1982
) and a number of PCP core pro-
teins and effectors have been identified afterward, the mechanisms whereby
PCP is regulated still remain to be identified. One of the challenges is to un-
derstand how Wnt ligands regulate PCP in vertebrates.
Secreted signaling molecules such as Fgf, Tgf-
b
, Hedgehog, or Wnt fam-
ily members can govern tissue patterning by forming extracellular protein
gradients. It was well understood that such gradients provide quantitative
information to generate different cell types and control cell proliferation
