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J. Biol. Chem., Vol. 281, Issue 41, 30794-30803, October 13, 2006

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Function of the Two Xenopus Smad4s in Early Frog Development^*

Chenbei Chang¹, Ali H. Brivanlou, and Richard M. Harland^¶

From the Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, the Laboratory of Molecular Embryology, Rockefeller University, New York, New York 10021, and the ^¶Department of Molecular and Cell Biology and Center for Integrative Genomics, University of California, Berkeley, California 94720-3200

Signals from the transforming growth factor family members are transmitted in the cell through specific receptor-activated Smads and a common partner Smad4. Two Smad4 genes ( and /10, or smad4 and smad4.2) have been isolated from Xenopus, and conflicting data are reported for Smad4/10 actions in mesodermal and neural induction. To further understand the functions of the Smad4s in early frog development, we analyzed their activities in detail. We report that Smad10 is a mutant form of Smad4 that harbors a missense mutation of a conserved arginine to histidine in the MH1 domain. The mutation results in enhanced association of Smad10 with the nuclear transcription corepressor Ski and leads to its neural inducing activity through inhibition of bone morphogenetic protein (BMP) signaling. In contrast to Smad10, both Smad4 and Smad4 enhanced BMP signals in ectodermal explants. Using antisense morpholino oligonucleotides (MOs) to knockdown endogenous Smad4 protein levels, we discovered that Smad4 was required for both activin- and BMP-mediated mesodermal induction in animal caps, whereas Smad4 affected only the BMP signals. Neither Smad4 was involved directly in neural induction. Expression of Smad4-MO in early frog embryos resulted in reduction of mesodermal markers and defects in axial structures, which were rescued by either Smad4 or Smad4. Smad4-MO induced only minor deficiency at late stages. As Smad4, but not Smad4, is expressed at high levels maternally and during early gastrulation, our data suggest that although Smad4 and Smad4 may have similar activities, they are differentially utilized during frog embryogenesis, with only Smad4 being essential for mesoderm induction.

Received for publication, July 25, 2006 , and in revised form, August 14, 2006.

^* This work was supported by National Institutes of Health Grant R01 HD43345. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 205-975-7229; Fax: 205-975-5648; E-mail: cchang{at}uab.edu.

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