251signaling is particularly involved in establishing “pre-neural” ectodermal fate in the
chick and is not sufficient for neural induction, whereas in Xenopus, BMP antago-
nism is largely sufficient in vivo (Wills et al. 2010 ; Pinho et al. 2011 ). Experiments
in mammalian embryonic stem cells indicate that culture under low density or Tgfb-
inhibited conditions can lead to neural development (Tropepe et al. 2001 ; Chambers
et al. 2009 ), largely supporting the default model in mammalian cells.
The relative roles of FGF signaling and/or Wnt antagonism may reflect species
level differences in the function of the organizer. The Xenopus organizer expresses
shisa2, an antagonist of Fzds and FGF receptors (Yamamoto et al. 2005 ). Shisa
homologues are not expressed in the organizer in chicken and mouse, although they
are expressed in anterior regions (Furushima et al. 2007 ; Hedge and Mason 2008 ).
Thus, FGF signaling may be less critical in Xenopus neural induction because it is
normally inhibited in the presumptive neural region. FGF signaling may contribute
to neural induction by inhibiting Smad1, through MAPK-mediated linker domain
phosphorylation (Pera et al. 2003 ), or by inducing the expression of various pre-
neural genes (Sheng et al. 2003 ; Pinho et al. 2011 ). In chick, non-organizer Wnt
signaling can promote BMP activity, both indirectly by inhibiting the ability of FGF
activity to repress Bmp expression and by acting more directly to promote BMP
activity (Wilson et al. 2001 ). This latter activity may occur at the level of C-terminally
phosphorylated active Smad1. FGF/MAPK and Gsk3b activity (i.e., absence of Wnt
signaling) can phosphorylate the linker region of active Smad1 leading to its turn-
over, whereas limiting MAPK activity of Wnt treatment can prolong active Smad1
signaling (Fuentealba et al. 2007 ).
In general, FGF may be more critical in cases where neural development occurs
over a longer time course and many rounds of cell divisions, as in the chick and
mouse. Additionally, FGFs may have different roles in the context of an epiblast
epithelial architecture (i.e., pseudostratified, interdigitating columnar epithelia). A
similar idea has come from experiments in embryonic stem cells, where FGF sig-
naling and low Wnt activity are thought to promote a pluripotent stem cell state
resembling the postimplantation epiblast (EpiSC) (reviewed in Ozair et al. 2012 ).
Thus FGFs may not just promote a “pre-neural” state, but a “pre-germ layer differ-
entiation” state, which would encompass neural fate.
6.4.3 Self-Organization and Developmental Plasticity
in the Organizer
In addition to the neural inducing and mesoderm patterning functions, the develop-
mental plasticity of the organizer can be largely explained by BMP regulation. Early
experiments by Spemann showed that partial constriction of the gastrula along the
midline led to double-headed tadpoles, each with a normally formed anterior axis
(Spemann 1903 ). Thus, half an organizer can restore normal bilateral symmetry locally
and scale its effects accordingly. Similarly, rather normal embryos develop from dor-
sal half explants as opposed to hyperdorsalized embryos, which would be the expected
result in the absence of self-organization (Reversade and De Robertis 2005 ).
6 Vertebrate Axial Patterning: From Egg to Asymmetry