Heterodimers reign in the embryo

Abstract

Experiments by three independent groups on zebrafish have clarified the role of two signaling factors, Nodal and Gdf3, during the early stages of development.

Keywords: Gdf3; Nodal signaling; axis formation; developmental biology; endoderm; left-right patterning; mesoderm; stem cells; zebrafish.

Figure 1.. Nodal homodimers and Nodal-Gdf3 heterodimers.

Gdf3 (red) and Nodal (blue) both contain an N-terminal prodomain and a mature C-terminal ligand when they are first synthesized in the endoplasmic reticulum. Nodal can form homodimers, and also heterodimers with Gdf3, but Gdf3 is unable to form homodimers. Although cells can form Nodal homodimers, Nodal-Gdf3 heterodimers predominate in signaling (after cleavage in the endoplasmic reticulum and secretion into the extracellular space).

Figure 2.. Nodal-Gdf3 signaling in zebrafish.

After being secreted, the mature Nodal-Gdf3 heterodimer (red and blue) diffuses through the extracellular space to the surface of the receiving cell, where it binds a co-receptor called Oep (short for one-eyed-pinhead; Gritsman et al., 1999) and two receptors (Acvr1b and Acvr2; Wrana et al., 1994) to assemble a signaling complex. Within this complex, the Acvr2 receptors phosphorylate the Acvr1b receptors, which in turn phosphorylate proteins called Smad2 and Smad3 (Gu et al., 1998; Dubrulle et al., 2015). The phosphorylated Smad2 or Smad3 then forms a heterotrimer with Smad4 and accumulates in the nucleus, where it activates the transcription of various genes. The signaling complex shown here was first suggested by Calvanese et al. (2010).