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activity can be seen in Xenopus embryos as a gradient of nuclear beta-catenin in the
prospective neural plate of the gastrula, with the highest levels posteriorly (Kiecker
and Niehrs 2001 ). Similarly, in the mouse gastrula, posterior gradients of Wnt
reporter construct activity have been observed (Maretto et al. 2003 ; Lewis et al.
2007 , 2008 ; Fossat et al. 2011 ). Experiments in neuralized Xenopus animal caps
showed that inducible expression of activated beta-catenin during gastrulation
directly induces posterior neural markers (McGrew et al. 1997 ; Domingos et al.
2001 ). Additionally, cell–cell contact and FGF signaling are required in this case,
suggesting the involvement of a “community-effect” response, as described for
muscle formation (Standley and Gurdon 2004 ). Similar requirements for Wnt and
FGF signaling were seen in chicken, where Wnt treatment directly and dose-
dependently posteriorizes competent anterior neural tissue explants (Nordstrom
et al. 2002 ). Correspondingly, Wnt inhibition in posterior neural explants causes
anteriorization. FGF signaling is also required for posterior specification, but likely
in a permissive role, acting in a non-dose-dependent fashion. And loss of FGF sig-
naling does not anteriorize posterior neural fates (Nordstrom et al. 2002 ). Wnt sig-
naling also has subsequent roles in specifying the posterior portion of major brain
subdivisions later in development, in particular distinguishing diencephalon versus
telencephalon (Heisenberg et al. 2001 ; Houart et al. 2002 ). It is therefore of great
interest to determine how this signaling system is compartmentalized and reiterated
during multiple aspects of individual tissue and organ development.
At the transcriptional level, Wnt/beta-catenin signaling during posterior specifi-
cation is thought to proceed through the use of Tcf/Lef proteins as coactivators.
This mechanism of gene activation is likely different from early, axis-inducing Wnt
signals, which involve mainly derepression of Tcf3 (see Sect. 6.3.1). In mouse
development, double homozygous genetic deletion of Lef1 and Tcf7(Tcf1) results
in posterior defects in addition to abnormalities in mesoderm specification (Galceran
et al. 1999 ). Similarly in Xenopus, Lef1 and Tcf1 are required for the late/ventral
response to Wnt (Roël et al. 2002 ; Liu et al. 2005 ), whereas Tcf3 is dispensable in
this regard (Hamilton et al. 2001 ). Recall that Tcf3 is necessary for the repression
of early Wnt target genes in vertebrates. Experiments in mouse and frog have sug-
gested a “Tcf exchange” model for the changes in target gene responses to Wnt
signaling prior to and following axis formation. Lef1 can be transcriptionally acti-
vated by Wnt signaling (chick, Skromne and Stern 2001 ; mouse, Wu et al. 2012a),
suggesting that cells experiencing Wnt signals undergo a qualitative change in their
potential underlying responses to subsequent Wnt exposure during development.
Similarly, early Tcf3 repressor function is inactivated by Wnt-activated kinases and
replaced by activating Tcf1 function in both Xenopus and in mouse embryonic stem
cells (Hikasa et al. 2010 ; Yi et al. 2011 ). Thus, the activation of genes during pos-
terior specification is likely to involve both beta-catenin-dependent derepression of
Tcf3, followed by replacement and activation by Lef1/Tcf1. In support of this idea,
mouse knock-ins in which Tcf3 has been replaced by the deltaNTcf3 construct
(non-derepressible) lack Lef1 expression and show defective late Wnt responses
(Wu et al. 2012a).
D.W. Houston