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Abstract
Smad6 and Smad7 comprise a subclass of vertebrate Smads that antagonize, rather than
transduce, TGF-beta family signaling. These Anti-Smads can block BMP signaling, as
evidenced by their ability to induce a secondary dorsal axis when misexpressed ventrally
in Xenopus embryos. Smad7 inhibits additional TGF-beta related pathways, and causes
spina bifida when misexpressed dorsally. We have performed structure-function analyses
to identify domains of Anti-Smads that are responsible for their shared and unique
activities. We find that the C-terminal domain of Smad7 displays strong axis inducing
activity but cannot induce spina bifida. The isolated N-terminal domain of Smad7 is
inactive but restores the ability of the C-terminus to cause spina bifida when the
two are co-expressed. By contrast, the N- and C-terminal domains of Smad6 have weak
axis inducing activity when expressed individually, but show full activity when co-expressed.
Chimeric analysis demonstrates that the C-terminal domain of Smad7, but not Smad6,
can induce spina bifida when fused to the N-terminal domain of either Smad6 or Smad7.
Thus, although the C-terminal domain is the primary determinant of the intrinsic activity
of Xenopus Anti-Smads, the N-terminal domain is essential for full activity, is interchangeable
between Smad6 and 7, and can function in trans.