Wnt Regulation of Planar Cell Polarity (PCP) - Current Topics in Developmental Biology - page 274

the Wnt5a morphogen gradient to extended cartilage along the P-D axis.
Besides the developing limb, it is very likely that in other developmental
processes such as the frontonasal elongation, A-P body axis extension, and
secondary palate fusion, Wnt5a gradient may also define a unidirectional
polarity ( Fig. 11.1B ). In all these places, Wnt5a is expressed in a graded
fashion (branchial arches, tail bud, and palatal mesenchyme) ( He et al.,
2008; Liu et al., 2012; Yamaguchi et al., 1999 ). Wnt5a and Vangl2 mutant
mice exhibited similar defects in these places ( Gao et al., 2011; Liu et al.,
2012, 2009; Yamaguchi et al., 1999 ). Biochemically, our finding of a
Wnt5a gradient leading to a Vangl2 phosphorylation gradient provides a
mechanism whereby Wnt5a signaling gradient elicits a graded response
( Gao et al., 2011 ), supporting the instructive role of Wnts ( Fig. 11.1A ).
Although the graded Wnt5a expression may be functionally important in
regulating PCP, more rigorous genetic assays are needed to directly test
whether Wnt5a acts instructively or permissively in controlling PCP.
Secreted frizzled-related protein (Sfrp) family members are homologous
to the extracellular domains of Frizzleds. They bind to and modulate activity
of Wnt proteins including Wnt5a. Disruption of certain Sfrp proteins causes
PCP-like phenotype in multiple tissues and they genetically interact with
Vangl2 ( Matsuyama, Aizawa, & Shimono, 2009; Satoh, Matsuyama,
Takemura, Aizawa, & Shimono, 2008; Sugiyama et al., 2010 ). In
addition, when Sfrp2 that potentially disturbs all Wnt signals is
misexpressed, it disrupted global alignment and orientation of lens fibers
in the eye, suggesting that Wnt ligands act as an extracellular directional
signal to polarize fibers in the eye lens ( Sugiyama et al., 2010 ). However,
while the Vangl2 is asymmetrically localized to the anterior pole side of
lens cells, the Wnt signal gradient is not well defined in the mammalian
eye development.
In the developing cochlea of the inner ear, four rows of sensory hair cells
reorient themselves from E17 to P10 to achieve a final uniform polarity.
Wnt7a is found to be highly expressed in the developing cochlea, and by
E16.5, it becomes restricted to pillar cells, which are supporting cells
between three outer rows and one inner row of hair cells. When in vitro -
cultured cochlea explants are exposed toWnt7a conditional medium, which
should theoretically disturb the potential morphogen gradient generated by
asymmetrically expressed endogenous Wnt7a in pillar cells, the reorientation
process of outer hair cells is inhibited. However, Wnt7a / mutant itself has
no obvious orientation defects, suggesting possible functional redundancy
from other Wnt s expressed in the cochlea ( Wnt5a , Wnt2 , Wnt10b , or more)