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First published online 27 April 2005
doi: 10.1242/dev.01842
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1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5,
Canada
2 Max-Planck Institute of Immunobiology, Department of Molecular Embryology,
Freiburg 79108, Germany
3 Kyoto University Graduate School of Medicine, Department of Pharmacology,
Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
4 University of Toronto, Department of Medical Genetics and Microbiology,
Toronto M5S 1A8, Canada
Author for correspondence (e-mail:
rossant{at}mshri.on.ca)
Accepted 30 March 2005
Differential gene regulation integrated in time and space drives developmental programs during embryogenesis. To understand how the program of gastrulation is regulated by Wnt/ß-catenin signaling, we have used genome-wide expression profiling of conditional ß-catenin mutant embryos. Known Wnt/ß-catenin target genes, known components of other signaling pathways, as well as a number of uncharacterized genes were downregulated in these mutants. To further narrow down the set of differentially expressed genes, we used whole-mount in situ screening to associate gene expression with putative domains of Wnt activity. Several potential novel target genes were identified by this means and two, Grsf1 and Fragilis2, were functionally analyzed by RNA interference (RNAi) in completely embryonic stem (ES) cell-derived embryos. We show that the gene encoding the RNA-binding factor Grsf1 is important for axial elongation, mid/hindbrain development and axial mesoderm specification, and that Fragilis2, encoding a transmembrane protein, regulates epithelialization of the somites and paraxial mesoderm formation. Intriguingly, the knock-down phenotypes recapitulate several aspects of Wnt pathway mutants, suggesting that these genes are components of the downstream Wnt response. This functional genomic approach allows the rapid identification of functionally important components of embryonic development from large datasets of putative targets.
Key words: Wnt/ß-catenin signaling, Gastrulation, RNA interference (RNAi), Target genes, Expression profiling, Grsf1, Fragilis2, Functional genomics
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