Signaling by NODAL is essential for patterning of the axes of the embryo and formation of mesoderm and endoderm (reviewed in Schier 2009, Shen 2007). The NODAL proprotein is secreted and cleaved extracellularly to yield mature NODAL. Mature NODAL homodimerizes and can also form heterodimers with LEFTY1, LEFTY2, or CERBERUS, which negatively regulate NODAL signaling. NODAL also forms heterodimers with GDF1, which increases NODAL activity. NODAL dimers bind the NODAL receptor comprising a type I Activin receptor (ACVR1B or ACVR1C), a type II Activin receptor (ACVR2A or ACVR2B), and an EGF-CFC coreceptor (CRIPTO or CRYPTIC). After binding NODAL, the type II activin receptor phosphorylates the type I activin receptor which then phosphorylates SMAD2 and SMAD3 (R-SMADs). Phosphorylated SMAD2 and SMAD3 form hetero-oligomeric complexes with SMAD4 (CO-SMAD) and transit from the cytosol to the nucleus. Within the nucleus the SMAD complexes interact with transcription factors such as FOXH1 to activate transcription of target genes.