Long-range action of Nodal requires interaction with GDF1

Abstract

GDF1 (growth/differentiation factor 1), a Vg1-related member of the transforming growth factor-beta superfamily, is required for left-right patterning in the mouse, but the precise function of GDF1 has remained largely unknown. In contrast to previous observations, we now show that GDF1 itself is not an effective ligand but rather functions as a coligand for Nodal. GDF1 directly interacts with Nodal and thereby greatly increases its specific activity. Gdf1 expression in the node was found necessary and sufficient for initiation of asymmetric Nodal expression in the lateral plate of mouse embryos. Coexpression of GDF1 with Nodal in frog embryos increased the range of the Nodal signal. Introduction of Nodal alone into the lateral plate of Gdf1 knockout mouse embryos did not induce Lefty1 expression at the midline, whereas introduction of both Nodal and GDF1 did, showing that GDF1 is required for long-range Nodal signaling from the lateral plate to the midline. These results suggest that GDF1 regulates the activity and signaling range of Nodal through direct interaction.

Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy

“…The long-range action of Nodal has been shown to require the formation of Nodal-Gdf1 heterodimers (17). Recent studies also suggest the interaction of Nodal and sulfated glycosaminoglycans (GAGs) play a role in the longrange propagation of Nodal signaling (30).…”

“…To further elucidate the underlying molecular mechanism, we examined the expression of Gdf1 and Cryptic. Gdf1 encodes a TGF␤ superfamily ligand required for Nodal long-range action, including propagation of Nodal signaling from the embryonic node to the LPM (17), while Cryptic, a coreceptor required for Nodal signal reception, is also essential for Nodal expression in the left LPM (18 Morpholino knockdown of Megf8 causes situs discordance of heart tube and foregut. Zebrafish embryos injected with control or Megf8 morpholinos were examined for heart and gut situs defects using RNA in situ hybridization analysis with Nkx2.5 (A-D) and Foxa3 (E-H) probes to visualize the heart tube and gut, respectively.…”

Activin/Nodal signalling before implantation: setting the stage for embryo patterning

“…Gdf1 and Gdf3, two other TGF-b family members, were found to bind the same receptor complex as Nodal, with the same requirement for an EGF-CFC co-receptor [21]. They are, however, unable to activate the Smad2/3 pathway on their own at physiological concentrations [22][23][24][25]. Instead, they seem to act as heterodimers, either to increase the range or strength of Nodal signalling when combined with Nodal, or to inhibit BMP signalling when combined with Bmp4 [22,[24][25][26].…”

“…They are, however, unable to activate the Smad2/3 pathway on their own at physiological concentrations [22][23][24][25]. Instead, they seem to act as heterodimers, either to increase the range or strength of Nodal signalling when combined with Nodal, or to inhibit BMP signalling when combined with Bmp4 [22,[24][25][26]. Further interactions between the two signalling pathways involve the inhibitory Smads, Smad6 and Smad7, which are themselves targets of Smad signalling and act either as general inhibitors of Smad-mediated signalling (Smad7), or inhibit more specifically the BMP pathway (Smad6) [27].…”

Hyperglycemia impairs left–right axis formation and thereby disturbs heart morphogenesis in mouse embryos

“…Nodal, which encodes a member of the TGF-β family of proteins, is one such gene, with the level of its expression being greater on the left side than on the right (28,29). Nodal produced in the crown cells forms a heterodimer with a TGF-β family member, growth differentiation factor 1 (GDF1), which increases its activity, and it is thought to diffuse to the lateral plate mesoderm (LPM) (30,31). Nodal activates intracellular signaling by binding to Activin receptors and Cryptic cofactor.…”