Biomedical Engineering Reference
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Another proposed mechanism is Frizzled gradient model, in which a
gradient of unknown signal sets up a Frizzled activity gradient across a
field of cells. Then, through the cross-cell Flamingo homodimers, each
cell compares the level of Frizzled activity with its adjacent cells and
orients itself toward its neighbor with lower Frizzled activity (
Lawrence
et al., 2004
). However, the nature of proposed upstream signal
establishing Frizzled activity gradient is not defined, either. In both
models, it is unknown what provides upstream global cues to break the
symmetry of PCP protein localization and initiate PCP. Since secreted
molecules generated from a localized source can form morphogen
gradients across a field of cells, morphogens that regulate formation of
body axes have been proposed to also act as global cues for PCP
(
Lawrence et al., 2007
). While major morphogens, such as Hedgehog
(Hh) and Decapentaplegic (Dpp), do not directly regulate PCP in
Drosophila
(
Strutt, 2009
), Wingless (Wg) has been hypothesized to
regulate PCP as its receptor, Frizzled (Fz), is one of the core PCP
proteins. However, extensive studies in fly so far failed to prove a role of
Wg in PCP (
Wu & Mlodzik, 2009
). Nevertheless, it remains a formal
possibility that Wg may exert its PCP regulatory function within a small
time window in which Wg's role in PCP and Wg/Armadillo signaling
can be cleanly separated.
In vertebrates, however, Wnt5b and Wnt11 are clearly required for CE
during gastrulation, a process regulated by PCP (
Heisenberg et al., 2000;
Rauch et al., 1997
). Zebrafish mutants
pipetail
(
ppt
,
wnt5b
) and
silberblick
(
slb
,
wnt11
) exhibit compromised CE movements with broadened and
shortened body axis, similar to the
trilobite
(
tri
) mutant caused by mutations
in the core PCP protein Vangl2 (
Heisenberg et al., 2000; Jessen et al.,
2002; Rauch et al., 1997
). In mammals, some Wnts, like Wnt5a and
Wnt11, transduce their signals predominantly through noncanonical
b
-catenin-independent pathways (
Schneider & Mercola, 2001; Topol
et al., 2003; Westfall et al., 2003
). Importantly, Wnt5a genetically interacts
with core PCP protein, Vangl2, in sensory hair cell orientation in inner
ear and neural tube closure, strongly supporting its role in regulating PCP
(
Qian et al., 2007
). The role of Wnt5a required for establishing PCP is
demonstrated in the developing limb, in which Wnt5a regulates PCP in
the forming chondrocytes along the P-D axis (
Fig. 11.1A
) and likely in
other places such as the frontonasal processes and CE along A-P axis
(
Fig. 11.1B
)(
Gao et al., 2011
). In chick embryos, skeletal muscle fibers are
well organized along the body A-P axis. Elongated myocytes are aligned
