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BMP-mediated transcriptional regulation is controlled by the formation of phos-
phorylated Smad1/Smad4 complexes and subsequent nuclear translocation and asso-
ciation with target promoters. In general, Smad-responsive cis-regulatory elements
are thought to mediate low affinity interactions and Smad-associated cofactors are
therefore required for specific target promoter interactions. Smad1-binding transcrip-
tional cofactors Znf423 (Oaz; Seoane et al. 2000 and Hivep1 (Human immunodefi-
ciency virus type I enhancer binding protein 1/Schnurri1; Yao et al. 2006 ) have been
characterized and facilitate binding of BMP-activated Smads to BMP-responsive
enhancer elements. These cofactors likely recruit general transcriptional activators or
repressors depending on the cellular or epigenetic context (Blitz and Cho 2009 ).
6.4.5 Complexity of Cross-Regulation Between BMP Signaling
and the Organizer
BMP signaling activates a conserved cascade of gene regulation involving several
immediate response genes, including the homeobox ventx genes, as well as msx1
and wnt8a (Gawantka et al. 1995 ; Schmidt et al. 1996 ; Ault et al. 1996 ; Ladher et al.
1996 ; Onichtchouk et al. 1996 ; Suzuki et al. 1997 ; Hoppler and Moon 1998 ), and a
secondary target, even-skipped homolog 1 (evx1/xhox3) (Ruiz i Altaba et al. 1991 ).
Additionally, Ventx and Gsc proteins cross-repress each other’s expression, mediat-
ing part of the negative feedback regulation of BMP and organizer gene expression
(Fainsod et al. 1994 ; Gawantka et al. 1995 ; Onichtchouk et al. 1996 ; Trindade et al.
1999 ; Sander et al. 2007 ). In the mesoderm, Brachyury homolog (T) provides an
essential input to ventx expression (and hence gsc repression) through its interaction
with Smad1 (Messenger et al. 2005 ). Interestingly, double inhibition of Ventx and
Gsc results in normal embryos (Sander et al. 2007 ) indicating that these proteins are
only strictly required to regulate each other, and that redundant mechanisms pattern
the axis in their absence. Multiple such independent and redundant cross-regulatory
interactions between Gsc-Ventx and other protein pairs likely would provide robust-
ness to dorsoventral patterning mechanisms.
Similar cross-regulatory loops exist in zebrafish (Nikaido et al. 1997 ; Melby
et al. 2000 ; Kawahara et al. 2000 ; Imai et al. 2001 ), although the Ventx genes have
undergone a unique evolutionary trajectory in other organisms (Scerbo et al. 2014 ).
These genes appear to have been lost in rodents and are only expressed in a limited
set of hematopoietic cells in humans (Rawat et al. 2010 ). The Ventxs bear ancient
homology to Nanog, a gene implicated in pluripotency and primitive endoderm
formation (Kozmik et al. 2001 ). Nanog may have been co-opted for some of the
functions of Ventx in mammals, including possibly Gsc repression (Vallier et al.
2009 ), whereas Ventx may have substituted for Nanog function in fish and amphib-
ians (Camp et al. 2009 ; Scerbo et al. 2012 ). This case is particularly likely in the
anuran lineage, which appears to have secondarily lost Nanog (Scerbo et al. 2014 ).
In spite of this reduced dependency on Ventx in mammals, cross-antagonism
between BMP signaling and Gsc in patterning the axis/primitive streak has been
D.W. Houston