Nodal·Gdf1 Heterodimers with Bound Prodomains Enable Serum-independent Nodal Signaling and Endoderm Differentiation

Abstract

Background: To generate active Nodal suited for directed stem cell differentiation, we purified it as a heterodimer with Gdf1. Results: Heterodimeric Nodal⅐Gdf1 copurified with their cleaved prodomains, potentiated receptor activation and endoderm differentiation, and enabled paracrine signaling in serum-free conditions. Conclusion: Cell-non-autonomous high Nodal signaling thresholds depend on low molecular weight heterodimers. Significance: Nodal⅐Gdf1 is a new reagent to differentiate endoderm.

Biochemical and Cellular Analysis Reveals Ligand Binding Specificities, a Molecular Basis for Ligand Recognition, and Membrane Association-dependent Activities of Cripto-1 and Cryptic

“…Molecular genetic studies have established a functional link between Cripto-1 and the TGF-␤ family ligand Nodal (4,22): Nodal co-immunoprecipitated with Cripto-1 and required Cripto-1 for signaling (9,13,(23)(24)(25)(26)(27)(28)(29). These findings have supported the idea that Cripto-1 and the EGF-CFC family are obligate Nodal "co-receptors" that potentiate Nodal signaling (3,30,31).…”

“…Together, these findings indicate that the function of Cripto-1 remains unclear. Although Cripto-1 has been widely investigated, less is known about Cryptic, except that it is also implicated in Nodal signaling (13,29,30).…”

Conserved and divergent expression patterns of markers of axial development in the laboratory opossum,Monodelphis domestica

“…a6). Inhibin βA, Inhibin βB, Gdf1 , and Gdf3 are TGF‐β genes that might substitute for Nodal functions in the opossum epiblast and hypoblast, though the functions of their orthologs in epiblast and hypoblast development are not well understood in eutherian embryos (Beattie et al, ; Vallier et al, ; Levine and Brivanlou, ; Fuerer et al, ; Pauklin and Vallier, ). None of these genes was expressed in the opossum embryos even at D8.5 (Fig.…”

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

“…33 These studies provoked intense research interest in the developmental role of GDF1, resulting in further discoveries of its coreceptors, coligands and other associated effectors. [34][35][36] Interestingly, GDF1 loss of function not only leads to left-right asymmetry but also contributes to congenital heart defects associated with perturbed TGF-β signaling, 37 and cardiac hypertrophy linked with upregulated MEK-ERK1/2 signaling. 38 Importantly, GDF1 mutations are clinically associated with recessively inherited right atrial isomerism) 39 and congenital heart defect risk.…”