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Many different ligands of the TGF-beta superfamily signal in the early Xenopus embryo and are required for the specification and patterning of the three germ layers as well as for gastrulation. Recent advances in the field are helping us understand how ligand activity is regulated both spatially and temporally, the mechanism by which the signals are transduced to the nucleus and how essentially the same signalling pathway can activate completely different sets of genes in different regions of the embryo.
Figure 1 TGF-β signalling pathways in early Xenopus
development. The BMP pathway is shown on
the left and the Activin-like signalling pathway is
on the right. The BMP type II receptor is
XBMPRII, and two BMP type I receptors are
known, a Xenopus ALK3 (also called BR, for
BMP receptor) and XALK2. The Activin type II
receptor is XActRIIB and the type I receptor is
XALK4. Multiple ligands are thought to interact
with the receptor pairs. Receptor activation
leads to phosphorylation and activation of
R-Smads, which are XSmad1 and XSmad5 for
the BMP receptors and XSmad2 and XSmad3
for the Activin receptors. XSmad2 and XSmad3
are thought to be recruited to the receptors by
the membrane-associated protein, SARA. The
R-Smads then form complexes with co-Smads,
which are the constitutively nuclear XSmad4β at
late blastula/early gastrula stages and XSmad4α
at later stages, which is probably predominantly
cytoplasmic in uninduced cells. Activated Smad
complexes are recruited to DNA via specific
transcription factors such as XOAZ for
Smad1/Smad4 complexes and XFast-1 or Mixer
for Smad2/Smad4 complexes. No recruiting
transcription factors are yet known for
Smad5/Smad4 or Smad3/Smad4 complexes.
The pathway is further regulated at different
points as shown. Ligand antagonists function
extracellularly, probably preventing ligand binding
to the receptor. The pseudoreceptor BAMBI is
incorporated into receptor complexes but does
not signal. Inhibitory Smads (XSmad6 and
XSmad7) can act at the level of the receptors or
in the case of Smad6, can also compete with
Smad4 for activated Smad1. Smurf1 is an E3
ubiquitin ligase that targets Smad1 for
degradation. (For details, see main text.)
Figure 2
Different transcription factor partners for
activated XSmad2/XSmad4β complexes are
expressed in different regions of the embryo.
In situ hybridizations to visualize (a) XFast-1,
(b) Mixer, or (c) XSmad2 mRNA (blue stain)
in stage 10.25 Xenopus embryos that had
been cut in half through the middle of the
dorsal lip. Arrowhead, dorsal blastopore lip.
XFast-1 mRNA is localized predominantly in
the animal cap and in the prospective
mesoderm throughout the marginal zone.
Mixer, in contrast, is excluded from these
regions and is expressed in a ring
predominantly in prospective endoderm,
and in involuting mesoderm. XSmad2
transcripts overlap with both the XFast-1 and
Mixer transcripts.
