Mesendoderm induction and reversal of left-right pattern by mouse Gdf1, a Vg1-related gene

TGF beta signals play important roles in establishing the body axes and ger m layers in the vertebrate embryo. Vg1 is a TGF beta -related gene that, du e to its maternal expression and vegetal localization in Xenopus, has recei ved close examination as a potential regulator of development in Xenopus, z ebrafish, and chick. However, a mammalian Vg1 ortholog has not been identif ied. To isolate mammalian Vg1 we screened a mouse expression library with a Vg1-specific monoclonal antibody and identified a single cross-reactive cl one encoding mouse Gdf1. Gdf1 is expressed uniformly throughout the embryon ic region at 5.5-6.5 days postcoitum and later in the node, midbrain, spina l cord, paraxial mesoderm, lateral plate mesoderm, and limb bud. When expre ssed in Xenopus embryos, native GDF1 is not processed, similar to Vg1. In c ontrast, a chimeric protein containing the prodomain of Xenopus BMP2 fused to the GDF1 mature domain is efficiently processed and signals via Smad2 to induce mesendoderm and axial duplication. Finally, right-sided expression of chimeric GDF1, but not native GDF1, reverses laterality and results in r ight-sided Xnr1 expression and reversal of intestinal and heart looping. Th erefore, GDF1 can regulate left-right patterning, consistent with the Gdf1 loss-of-function analysis in the mouse (C. T. Rankin, T. Bunton, A. M. Lawl er, and S. I. Lee, 2000, Nature Genet. 24, 262-265) and a proposed role for Vg1 in Xenopus. Our results establish that Gdf1 is posttranslationally reg ulated, that mature GDF1 activates a Smad2-dependent signaling pathway, and that mature GDF1 is sufficient to reverse the left-right axis. Moreover, t hese findings demonstrate that GDF1 and Vg1 are equivalent in biochemical a nd functional assays, suggesting that Gdf1 provides a Vg1-like function in the mammalian embryo. (C) 2000 Academic Press.