231and/or antagonism of the Wnt/beta-catenin pathway (Rauch et al. 1997 ; Rothbächer
et al. 2000 ; Wallingford et al. 2000 ; Veeman et al. 2003a) (Fig. 6.7). In vertebrates,
these beta-catenin-independent Wnt pathways (often referred to, malapropos, as the
“noncanonical” Wnt pathways) were shown to act through conserved Drosophila
planar cell polarity (PCP) homologs and/or through release of intracellular calcium
(Wnt/PCP and Wnt/Calcium pathways). Although these different pathway desig-
nations are convenient conventions, there is likely a large degree of overlap and
interaction among them in vivo, particularly in the case of the Wnt/PCP and Wnt/
Calcium pathways, and the ultimate outcome of signaling is likely dependent on the
complement of Fzd receptors and coreceptors present on a given cell. This impor-
tant point was exemplified early on by experiments showing that Wnt5a, tradition-
ally considered a beta-catenin-independent Wnt ligand, could induce second axes
in Xenopus when co-expressed with its cognate receptor Frizzled 5 (He et al. 1997 ),
and recently by studies demonstrating Wnt5a-mediated regulation of beta-catenin-
dependent and -independent Wnt signaling in mammals (Mikels and Nusse 2006 ;
van Amerongen et al. 2012 ).
PCP signaling in vertebrates involves a set of components largely homologous to
those mediating planar cell polarity signaling during imaginal disc development in
insects (Vinson and Adler 1987 ; Krasnow and Adler 1994 ). This core set of proteins
controls asymmetric Fzd1 localization (Strutt 2001 ) independently of Wnt ligands
(Lawrence et al. 2002 ) and have been characterized genetically and biochemically in
Drosophila (reviewed in Maung and Jenny 2011 ; Jose Maria Carvajal-Gonzalez
2014 ). These proteins include Fzd, Dishevelled, Flamingo (Fmi, a seven transmem-
brane pass cadherin), Prickle (Pk, a LIM and PET domain protein), strabismus/Van
Gogh (Stbm/Vang, a four transmembrane protein with a PDZ motif), and Diego
(Dgo, an ankyrin repeat protein). Homologous proteins also control epithelial cell
and tissue polarity in vertebrates, notably in the inner ear (reviewed in Veeman et al.
2003a; Bayly and Axelrod 2011 ). Additionally, vertebrate PCP proteins are critical
for controlling cell shape and cell migration in mesenchymal-type cells. Cell interca-
lation and cell migration during vertebrate gastrulation and neurulation in particular
are dependent on Wnt/PCP signaling (reviewed in Solnica-Krezel and Sepich 2012 ).
The mechanisms of signal transduction during Wnt/PCP signaling in vertebrates
are more varied and less well characterized than those of the beta-catenin-dependent
pathway. Activation of the Wnt/PCP pathway in vertebrates is dependent on certain
Wnt-Fzd combinations and a different set of coreceptors instead of Lrp5/6, includ-
ing Ryk (Kim et al. 2008 ; Yoshikawa et al. 2003 ), Ror2 (Schambony and Wedlich
2007 ; Gao et al. 2011 ), and various Glypican proteoglycans (Topczewski et al.
2001 ; Ohkawara et al. 2003 ). Additionally, the transmembrane protein encoding
Protein tyrosine kinase 7 (Ptk7) has been characterized as a novel regulator of PCP
signaling (Lu et al. 2004 ; Yen et al. 2009 ). The role of Ptk7 is unclear, but it may
represent an additional Wnt coreceptor modulating beta-catenin inhibition and acti-
vation with PCP signaling (Peradziryi et al. 2011 ; Hayes et al. 2013 ; Bin-Nun et al.
2014 ; Linnemannstöns et al. 2014 ). Dvl involvement is also critical for beta-catenin-
independent Wnt signaling, although different domains are important for each func-
tion by controlling protein complex assembly and subcellular localization (Axelrod
6 Vertebrate Axial Patterning: From Egg to Asymmetry