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Science 298 (5600): 1996-1999

Copyright © 2002 by the American Association for the Advancement of Science

Inhibition of Excess Nodal Signaling During Mouse Gastrulation by the Transcriptional Corepressor DRAP1

Rabah Iratni,1*dagger Yu-Ting Yan,2* Canhe Chen,2 Jixiang Ding,2 Yi Zhang,1ddagger Sandy M. Price,2 Danny Reinberg,1§ Michael M. Shen2§

The formation and patterning of mesoderm during mammalian gastrulation require the activity of Nodal, a secreted mesoderm-inducing factor of the transforming growth factor-beta (TGF-beta ) family. Here we show that the transcriptional corepressor DRAP1 has a very specific role in regulation of Nodal activity during mouse embryogenesis. We find that loss of Drap1 leads to severe gastrulation defects that are consistent with increased expression of Nodal and can be partially suppressed by Nodal heterozygosity. Biochemical studies indicate that DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription factor FoxH1 (FAST), a critical component of a positive feedback loop for Nodal activity. We propose that DRAP1 limits the spread of a morphogenetic signal by down-modulating the response to the Nodal autoregulatory loop.

1 Howard Hughes Medical Institute and Department of Biochemistry, Division of Nucleic Acids Enzymology,
2 Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854, USA.
*   These authors contributed equally to this work.

dagger    Present address: Institute Albert Bonniot, Domaine de la Merci, 38706 La Tronche Cedex, France.

ddagger    Present address: Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.

§   To whom correspondence should be addressed. E-mail: reinbedf{at}umdnj.edu, mshen{at}cabm.rutgers.edu



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