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Wnt ligands and the typical PCP phenotypes of the Frizzled1/2 and
Frizzled3/6 mutant mice ( Wang et al., 2006; Yu et al., 2010 ). Frizzleds
recruit Disheveled family proteins, which then further transduce signals
to downstream components. Elegant genetics analysis confirmed their
essential roles in PCP pathway in mammalian development ( Etheridge
et al., 2008; Hamblet et al., 2002; Wang et al., 2006 ). However, Frizzleds
and Disheveleds are not only dedicated to PCP pathway, but they are also
indispensable for Wnt/ b -catenin signaling, which hampers mechanistic
studies of the Wnt/PCP pathway through manipulating Frizzled/
Disheveled. In contrast, Vangl1 and Vangl2 are dedicated to the PCP
pathway ( Song et al., 2010 ). Therefore, the regulatory mechanisms of PCP
can be readily studied in Vangl1 and Vangl2 mutants. In addition to
Frizzleds, some atypical Wnt receptors, including Ror2, Ryk, and Ptk7,
have also been implicated in mediating Wnt signaling ( Fig. 11.2 ).
Ror2, a single transmembrane receptor tyrosine kinase, was well
established to mediate Wnt5a signal both in vitro and in vivo ( Green,
Kuntz, & Sternberg, 2008; Minami, Oishi, Endo, & Nishita, 2010 ).
Wnt5a inhibits Wnt/ b -catenin signals through Ror2 ( Mikels & Nusse,
2006 ), and Ror2 / mice is similar to, although less severe than, the
Wnt5a / mutant. Both mutant mice display similar phenotypes of
dwarfism, flat face, short limbs and tails, and some other defects
( DeChiara et al., 2000; Gao et al., 2011; Oishi et al., 2003; Takeuchi
et al., 2000; Yamaguchi, Bradley, McMahon, & Jones, 1999; Yang,
Topol, Lee, & Wu, 2003 ). In addition, mutations in both ROR2
and WNT5A are identified to cause Robinow syndrome, which is
characterized by short-limbed dwarfism, abnormalities in the head, face,
and external genitalia, as well as vertebral segmentation ( Afzal & Jeffery,
2003; Afzal et al., 2000; Person et al., 2010; van Bokhoven et al., 2000 ).
Not surprisingly, Ror2, like its ligand Wnt5a, also genetically interacts
with Vangl2 ( Gao et al., 2011; Qian et al., 2007 ). When Vangl2 was
further removed in the Ror2-null background, double knockout mice
exhibited nearly identical phenotypes compared to the Wnt5a / mutant
in many places, including shortened limbs, tails, and craniofacial processes
( Gao et al., 2011 ). These defects together with biochemical studies which
have identified Wnt5a-induced complex formation between Ror2 and
Vangl2 indicated that Wnt5a transduces its signal through Ror2 and
Vangl2 to regulate PCP ( Gao et al., 2011 ). A very recent report showed
that Ror1 and Ror2 double knockout mice displayed exencephaly
(indicating a PCP phenotype) at a low penetrance and died at E15.5. The
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