Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning.
Vertebral bodies are segmented along the anteroposterior (AP) body axis, and the segmental identity of the vertebrae is determined by the unique expression pattern of multiple Hox genes. Recent studies have demonstrated that a transforming growth factor beta (TGF-beta) family protein, Gdf11 (growth and differentiation factor 11), and the activin type II receptor, ActRIIB, are involved in controlling the spatiotemporal expression of multiple Hox genes along the AP axis, and that the disruption of each of these genes causes anterior transformation of the vertebrae. Skeletal defects are more severe in Gdf11-null mice than in ActRIIB-null mice, however, leaving it uncertain whether Gdf11 signals via ActRIIB. Here we demonstrate using genetic and biochemical studies that ActRIIB and its subfamily receptor, ActRIIA, cooperatively mediate the Gdf11 signal in patterning the axial vertebrae, and that Gdf11 binds to both ActRIIA and ActRIIB, and induces phosphorylation of Smad2. In addition, we also show that these two receptors can functionally compensate for one another to mediate signaling of another TGF-beta ligand, nodal, during left-right patterning and the development of anterior head structure.
Oh
S Paul
SP
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610, USA. ohp@phys.med.ufl.edu
Yeo
Chang-Yeol
CY
Lee
Youngjae
Y
Schrewe
Heindrich
H
Whitman
Malcolm
M
Li
En
E
D030301:Activin Receptors, Type II / Q000502:physiology*; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055412:Growth Differentiation Factors; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D018398:Homeodomain Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; C425584:activin receptor type II-B