Leading Wnt down a PCP Path:
Cthrc1 Acts as a Coreceptor in the Wnt-PCP Pathway
Matthew W. Kelley1,*
1Section on Developmental Neuroscience, National Institute on Deafness and Other Communication Disorders,
NIH, Bethesda, MD 20892, USA
Wnt signaling regulates many aspects of development through canonical and PCP signaling pathways. A
paper by Yamamoto et al. in this issue of Developmental Cell identifies collagen triple helix repeat containing
1 as a Wnt-binding cofactor that specifically activates the Wnt-PCP pathway.
The Wnt signaling pathway controls myr-
iad developmental events including cell
proliferation, migration, patterning, fate,
and differentiation. Many Wnt-mediated
events are regulated through a canonical
pathway in which binding of a Wnt to
tion of b-catenin. However, in other con-
texts, Wnt-Fz binding leads to activation
of an alternate pathway that acts through
a different set of signaling molecules to
regulate planar cell polarity (PCP) and
related developmental events. PCP refers
to the uniform orientation of a particular
aspect of a group of cells, usually within
an epithelial plane. The most obvious
examples of PCP are the orientation of
actin-based hairs along the wing and
body of Drosophila, the orientation of
hair follicles on the vertebrate body and
the orientation of mechanosensory hair
cells in the mammalian auditory sensory
epithelium, the organ of Corti. While
a role for wg, the Drosophila homolog of
Wnt, in PCP has not been demonstrated,
loss of Wnt function clearly disrupts PCP
in vertebrates (reviewed in Karner et al.,
2006). Results from genetic deletion stud-
ies in mice have indicated that specific
Wnt and Fzd genes mediate PCP signal-
ing (Wang et al., 2006). However, bio-
chemical studies suggest that Wnt-Fzd
interactions may be fairly promiscuous
with limited evidence for formation of
specific ligand-receptor pairs (reviewed
in Kikuchi et al., 2007).
These results are consistent with a role
for cofactors in mediating Wnt-Fzd inter-
actions and subsequent pathway activa-
tion. Previous results have identified
LRP5/6 and Ror2, an orphan receptor
tyrosine kinase with a Fzd-like CRD extra-
cellular binding domain, as coreceptors
for activation of the canonical and PCP
pathways, respectively (Hikasa et al.,
2002). However, since Wnts are secreted
while Fzds, LRPs, and Ror2 are mem-
brane bound, it seemed possible that ad-
ditional, secreted molecules might also
act as Wnt coreceptors. The paper by
Yamamoto et al. (2008) in this issue of
Developmental Cell demonstrates that
collagen triple helix repeat containing 1
(Cthrc1), a chordate-specific, secreted
glycoprotein, acts a key cofactor for for-
mation of Wnt/Fzd/Ror2 complexes and
for activation of the PCP pathway. The
authors utilize a novel interaction assay
referred to as coculture IP to examine
the interactions between Cthrc1, Wnts,
Fzds,LRPs, and Ror2and to demonstrate
that Cthrc1 interacts withWnt and Ror2 to
inhibit the canonical pathway. Moreover,
the authors demonstrate that the bio-
logical activity of Cthrc1 is restricted to a
highly conserved 200 amino acid C-termi-
thors generated Cthrc1 mutant mice and
examined the polarization of mechano-
sensory hair cells in the inner ear. PCP
was normal, but this was not that surpris-
ing considering the extensive functional
redundancy in vertebrate PCP (Wang
et al., 2006). However when Cthrc1 was
deleted in a Vangl2 heterozygous animal,
significant PCP defects were observed,
demonstrating a strong genetic interac-
tion between Cthrc1 and the core PCP
gene Vangl2. Similar phenotypes were
observed in Ror2 mutants, supporting
the conclusion that Cthrc1 promotes acti-
vation of the Wnt-PCP pathway. Unfortu-
nately, inner-ear phenotypes consistent
with an increase in canonical Wnt signal-
ing, such as an increase in the overall
size of the ear (Ohyama et al., 2006) or a
decrease in the ventral region of the ear
(Riccomagno et al., 2005) were not ex-
amined. Nor were any other phenotypes
that might have been consistent with
increased canonical signaling.
The demonstration that Wnt is required
for PCP in the cochlea further supports
the hypothesis that there are fundamental
differences in the requirement for Wnt/wg
in PCP between vertebrates and flies.
Wnt-dependent defects in PCP during
gastrulation, neurulation and in mech-
anosensory hair cell orientation, clearly
demonstrate a requirement for Wnt in
vertebrate PCP. This conclusion invari-
ably invokes contemplation about the po-
tential role of Wnts as morphogens. Both
Wnt5a and Wnt7a are asymmetrically
expressed on one side of the developing
organ of Corti, suggesting the potential
existence of a gradient of Wnt protein
(Dabdoub et al., 2003; Qian et al., 2007).
However, while previous results have
demonstrated defects in PCP in response
to the creation of a uniform concentration
of Wnt in vitro (Dabdoub et al., 2003; Qian
et al., 2007), attempts to reverse the gra-
dient, with the prediction that this would
lead to a reversal in the orientation of
cochlear PCP, have, to date, been largely
Genetic deletion of either Ror2 or
Cthrc1 resulted in a variable or non exis-
or limited inner ear phenotypes have been
observed for other vertebrate PCP genes
such as Scrb1 and Wnt5a. In contrast,
mutations in core PCP genes such as
Vangl2 (Montcouquiol et al., 2003), result
in severe defects while deletion of mild
PCP genes in a Vangl2 heterozygous
Developmental Cell 15, July 2008 ª2008 Elsevier Inc.
background often demonstrate strong
genetic interactions (Qian et al., 2007;
Yamamoto et al., 2008). These results
suggest that while single core PCP genes
act as the final common effectors of this
pathway in vertebrates, other aspects of
PCP are regulated through redundant
genes, such as Fzd3/6 and Dvl1/2. More-
over, a number of novel factors, including
Cthrc1, have been recruited to act as im-
portant regulatory cofactors.
In summary, the results of the study by
Yamamoto et al. (2008) identify the
secreted collagen glycoprotein, Cthrc1,
as a novel Wnt coreceptor that acts to
specifically cluster Wnts with Ror2 and
way. These results further support the
hypothesis that Wnts play a key role in
vertebrate PCP and suggest that the con-
served C-terminal region of Cthrc1 may
provide valuable clues in the identification
of additional Wnt cofactors.
Montcouquiol, M., Sassoon, D.A., Hseih, J.C., Ru-
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A New Kid on the TGFb Block: TAZ Controls
Smad Nucleocytoplasmic Shuttling
Katharine H. Wrighton,1Fangyan Dai,1and Xin-Hua Feng1,*
1Michael E. DeBakey Department of Surgery, Department of Molecular and Cellular Biology, Baylor College of Medicine,
One Baylor Plaza, Houston, TX 77030, USA
A recent study from Varelas et al. in Nature Cell Biology reveals a role for the transcriptional regulator TAZ in
TGFb signaling. Not only does TAZ couple phospho-Smads to the transcriptional machinery, it is also essen-
tial for their nuclear accumulation.
Transforming growth factor beta (TGFb)
signaling controls diverse developmental
processes and the pathogenesis of many
diseases. A key step in TGFb signaling
R-Smads (Smad2/3 in TGFb signaling;
Smad1/5/8 in BMP signaling), which is
mediated by serine/threonine kinase re-
ceptors. R-Smad phosphorylation allows
their hetero-oligomeric complex forma-
tion with Smad4 and the nuclear accumu-
lation of this complex, which ultimately
regulates gene transcription in conjunc-
tion with a variety of transcriptional cofac-
tors. Smad transcriptional cofactors have
largely been thought to play a role in pro-
moting signaling after Smads enter the
nucleus (Figure 1; Feng and Derynck,
2005; Schmierer and Hill, 2007).
Although it has been reported that
TGFb favors nuclear import of phospho-
R-Smads by enhancing their association
with the nuclear import factor importin-
b and/or disassociation from cytoplasmic
retention factors such as SARA, live cell
microscopy suggests TGFb does not af-
fect the nuclear import rate of Smad2
(Schmierer and Hill, 2007). In fact, accu-
mulation of phospho-Smads in the nu-
cleus in response to TGFb has been
shownto resultfromdecreased Smadnu-
clear export, suggesting activated Smads
may be held in the nucleus by retention
factors (Schmierer and Hill, 2007). In the
current issue of Nature Cell Biology,
Jeffrey Wrana and colleagues (Varelas
et al., 2008) present data suggesting that
the transcriptional regulator TAZ/WWTR1
has an essential role in Smad nuclear re-
tention, as well as in coupling Smads to
(Barrios-Rodiles et al., 2005). Varelas et al.
extended this finding and found that
TAZ associated with heteromeric Smad
complexes in a TGFb-dependent manner.
Knockdown of TAZ using siRNA markedly
reduced TGFb-induced transcription and
upregulation of TGFb target genes such
and PAI-I promoters, suggesting TAZ may
be involved in TGFb signaling at sites of
So, how does TAZ influence TGFb sig-
naling? TAZ depletion did not interfere
Developmental Cell 15, July 2008 ª2008 Elsevier Inc.