title: The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo.
abstract: The formation of the anterior visceral endoderm (AVE) in the pre-gastrulation mouse embryo represents a crucial event in patterning of the anterior-posterior axis. Here, we show that the transforming growth factor beta (Tgfbeta) family member Gdf3 (growth-differentiation factor 3), a close relative of Xenopus Vg1, resembles the Tgfbeta ligand Nodal in both its signaling activity and its role in AVE formation in vivo. Thus, in cell culture, Gdf3 signaling requires the EGF-CFC co-receptor Cripto and can be inhibited by Lefty antagonists. In Xenopus embryos, Gdf3 misexpression results in secondary axis formation, and induces morphogenetic elongation and mesendoderm formation in animal caps. In mouse embryos, Gdf3 is expressed in the inner cell mass and epiblast, and null mutants frequently exhibit abnormal formation or positioning of the AVE. This phenotype correlates with defects in mesoderm and definitive endoderm formation, as well as abnormal Nodal expression levels. Our findings indicate that Gdf3 acts in a Nodal-like signaling pathway in pre-gastrulation development, and provide evidence for the functional conservation of Vg1 activity in mice.
authors.affiliation: Center for Advanced Biotechnology and Medicine and Department of Pediatrics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
authors.forename: Canhe
authors.initials: C
authors.lastname: Chen
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Dianne E
authors.initials: DE
authors.lastname: Houston-Hawkins
authors.forename: Raymond
authors.initials: R
authors.lastname: Habas
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shen
authors.forename: Chester W
authors.initials: CW
authors.lastname: Brown
mesh_terms: D000818:Animals; D001483:Base Sequence; D001755:Blastocyst / Q000378:metabolism*; D019521:Body Patterning; D018076:DNA, Complementary / Q000235:genetics; D004707:Endoderm / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055451:Growth Differentiation Factor 3; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D055457:Nodal Protein; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D018076:DNA, Complementary; C525974:GDF3 protein, human; C525975:Gdf3 protein, mouse; D055451:Growth Differentiation Factor 3; D008562:Membrane Glycoproteins; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; C526008:Nodal protein, mouse; D011994:Recombinant Proteins; C489450:Tdgf1 protein, mouse; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor