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spliceform- dependent activator and repressive functions (Pukrop et al. 2001 ; Gradl
et al. 2002 ; Wöhrle et al. 2007 ; Weise et al. 2010 ).
This protein family has diverged in function, with Tcf3 primarily performing a
repressive role during early development and others acting as beta-catenin- dependent
co-activators later in development (see Sect. 6.5.3). Tcf3 constructs lacking the abil-
ity to interact with beta-catenin, by deletion of the N-terminal beta-catenin-binding
domain (deltaNTcf3), have been used to inhibit Wnt/beta-catenin- regulated tran-
scription, as these cannot be derepressed or activated by beta-catenin. Expression of
deltaNTcf3 during the cleavage stages efficiently ventralizes embryos (Molenaar
et al. 1996 ; Pelegri and Maischein 1998 ), but fails to inhibit ventrolateral develop-
ment or to block a late Wnt overexpression effect in Xenopus (i.e., anterior trunca-
tions; Hamilton et al. 2001 ). Additionally, experimental depletion of Tcf3 is sufficient
to activate Wnt target gene expression during vertebrate axis development (Kim et al.
2000 ; Houston et al. 2002 ; Dorsky et al. 2003 ; Merrill et al. 2004 ) and in embryonic
stem cells (Yi et al. 2008 ). Recent data from mouse studies in which the mutant del-
taNTcf3 was knocked into the endogenous Tcf7l1 locus have substantiated the idea
that Tcf3-mediated repression is critical for its role in early development (Wu et al.
2012a). Gastrulation proceeded normally in these mice, suggesting that the proper
amount of transcriptional derepression of Tcf3 targets can occur in the absence of
beta-catenin-Tcf3 interactions during axis formation. However, beta-catenin interac-
tions with Tcf3 and with other Lef1/Tcf7 proteins are required later in development
and in cancer cells (Wu et al. 2012a; Shy et al. 2013 ).
Derepression of Tcf3 is sufficient for Wnt target gene activation, although co-
activators are also required for normal development, suggesting both likely operate
in vivo. Beta-catenin recruits a number of co-activators including p300 and the con-
served nuclear complex containing Pygopus and Bcl9 proteins (Kramps et al. 2002 ;
Parker et al. 2002 ; Belenkaya et al. 2002 ). Pygo/Bcl9 are thought to be dedicated to
Wnt signaling and may regulate the extent that Tcfs and beta-catenin associate with
chromatin (Hoffmans et al. 2005 ; Fiedler et al. 2008 ; Mieszczanek et al. 2008 ). Also,
beta-catenin has also been implicated in establishing poised chromatin architecture
prior to major zygotic gene activation. Evidence in Xenopus suggests that beta-
catenin recruits Histone H3 Arginine 8 Methyltransferase (Prmt2; Blythe et al. 2010 )
to modify chromatin at target loci prior to the onset of target gene expression. Thus,
Wnt target genes are regulated both by direct transcriptional activation following
beta-catenin recruitment and by beta-catenin-regulated changes to chromatin, modes
of regulation that may be temporally uncoupled. It is unclear, however to what extent
the Pygo-regulated mechanisms and Prmt2 chromatin modifications are interrelated
or instead exhibit overlapping or redundant regulation of Wnt targets genes.
6.3.1.3 Wnt/Planar Cell Polarity (PCP) Signaling
The first studies on Wnt signaling focused on the regulation of beta-catenin in devel-
opment and cancer. Subsequent work found additional roles for a subset of Wnt
ligands other components in controlling cell movements during axis organization
D.W. Houston