Smads are central mediators of signal transduction for the TGF beta superfa
mily. However, the precise functions of Smad-mediated signaling pathways in
early development are unclear. Here we demonstrate a requirement for Smad2
signaling in dorsoanterior axis formation during Xenopus development. Usin
g two point mutations of Smad2 previously identified in colorectal carcinom
as, we show that Smad2 ushers Smad4 to the nucleus to form a transcriptiona
l activation complex with the nuclear DNA-binding protein FAST-1 and that t
he mutant proteins interact normally with FAST-1 but fail to recruit Smad4
into the nucleus. This mechanism of inhibition specifically restricts the d
ominant-negative activity of these mutants to the activin/Vg1 signaling pat
hway without inhibiting BMPs. Furthermore, expression of these mutants in X
enopus animal caps inhibits but does not abolish activin and Vg1 induction
of mesoderm and in the embryo results in a truncated dorsoanterior axis. Th
ese studies define a mechanism through which mutations in Smad2 may block T
GF beta-dependent signaling and suggest a critical role for inductive signa
ling mediated by the Smad2 pathway in Xenopus organizer function. (C) 1999
Academic Press.