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First published online 23 June 2004
doi: 10.1242/dev.01248
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1 Department of Molecular and Cellular Biology, Harvard University, Cambridge,
MA 02138, USA
2 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115,
USA
* Author for correspondence (e-mail: ejrobert{at}fas.harvard.edu)
Accepted 27 April 2004
Genetic and biochemical data have identified Smad4 as a key intracellular effector of the transforming growth factor ß (TGFß superfamily of secreted ligands. In mouse, Smad4-null embryos do not gastrulate, a phenotype consistent with loss of other TGFß-related signaling components. Chimeric analysis reveals a primary requirement for Smad4 in the extra-embryonic lineages; however, within the embryo proper, characterization of the specific roles of Smad4 during gastrulation and lineage specification remains limited. We have employed a Smad4 conditional allele to specifically inactivate the Smad4 gene in the early mouse epiblast. Loss of Smad4 in this tissue results in a profound failure to pattern derivatives of the anterior primitive streak, such as prechordal plate, node, notochord and definitive endoderm. In contrast to these focal defects, many well-characterized TGFß- and Bmp-regulated processes involved in mesoderm formation and patterning are surprisingly unaffected. Mutant embryos form abundant extra-embryonic mesoderm, including allantois, a rudimentary heart and middle primitive streak derivatives such as somites and lateral plate mesoderm. Thus, loss of Smad4 in the epiblast results not in global developmental abnormalities but instead in restricted patterning defects. These results suggest that Smad4 potentiates a subset of TGFß-related signals during early embryonic development, but is dispensable for others.
Key words: Smad4, TGFß, Anterior primitive streak, Mesoderm patterning, Mouse
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