263Nodal and BMP signaling also interact at several different levels. Nodal and
certain BMPs can form inactive heterodimeric ligands that fail to stimulate either
signaling pathway and exhibit mutual antagonism (Yeo and Whitman 2001 ). Also,
in the frog organizer Nodal and Admp (a BMP ligand) form a self-regulating net-
work to control anteroposterior patterning (Inui et al. 2012 ). Nodal and Admp can
compete for a shared receptor, Acvr2a, to oppositely regulate Nodal and Wnt antag-
onists in the anterior endoderm. High Nodal levels activate high expression of Nodal
antagonists, which subsequently block Nodal-Acvr2a interaction and permit the
occupancy by Admp. This alternate pathway limits the expression of Nodal antago-
nists, allowing Nodal signaling to reengage (Inui et al. 2012 ). Interestingly, Admp
depletion results in the anterior endoderm gaining head-inducing activity in Einsteck
transplantation assays, owing to overproduction of Nodal and Wnt antagonists (Inui
et al. 2012 ). The high degree of interrelatedness of these signaling pathways thus
can underlie many of the self-organizing properties of early axis formation.
6.5.3 Regulation of Posterior Development by Wnt Signaling
6.5.3.1 Default Specification of Anterior Neural Fate
In line with the activation-transformation model, experimental neural induction in
Xenopus animal caps (ectoderm), either by Noggin treatment (Lamb et al. 1993 ) or
by disaggregation (Grunz and Tacke 1989 , 1990 ), results exclusively in anterior
neural induction. Additionally, anteroposterior patterning is maintained in frog
embryos lacking mesoderm and endoderm, generated by vegt depletion or CerS
overexpression (Zhang et al. 1998 ; Wessely et al. 2001 ), and in those lacking both
organizer and ventral BMP signals (Reversade and De Robertis 2005 ). Similarly in
zebrafish, embryos lacking Nodal signaling and thus mesendoderm also retain ante-
rior identity in the ectoderm (Gritsman et al. 2000 ). In the mouse, loss of Nodal
signaling results in anterior neural specification in the epiblast in the absence of
mesendoderm and the AVE (Conlon et al. 1994 ; Brennan et al. 2001 ; Camus et al.
2006 ). The molecules mediating this anterior default state are not known but are
hypothesized to be present maternally in fish and amphibians and in the early epi-
blast of amniotes. Because embryonic stem cells can also acquire anterior neural
fates by default (Tropepe et al. 2001 ; Chambers et al. 2009 ), it is possible that core
pluripotency factors or proteins activated at the onset of epiblast differentiation
would be good candidates for anterior specifiers.
6.5.3.2 Graded Wnt Signals and Posterior Specification
Although many different signaling molecules have been implicated in posterior
neural fate specification, current evidence suggests that the graded activity of Wnt
signaling is the critical proximate determinant of early posterior identity. Wnt
6 Vertebrate Axial Patterning: From Egg to Asymmetry