Oh S Paul, Yeo Chang-Yeol, Lee Youngjae, Schrewe Heindrich, Whitman Malcolm, Li En
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Genes Dev. 2002 Nov 1;16(21):2749-54. doi: 10.1101/gad.1021802.
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.
椎体沿前后（AP）体轴进行分段，而椎骨的节段身份由多个Hox基因的独特表达模式决定。最近的研究表明，一种转化生长因子β（TGF-β）家族蛋白Gdf11（生长分化因子11）和激活素II型受体ActRIIB参与控制多个Hox基因沿AP轴的时空表达，并且这些基因中任何一个的破坏都会导致椎骨向前转化。然而，Gdf11基因敲除小鼠的骨骼缺陷比ActRIIB基因敲除小鼠更严重，因此尚不确定Gdf11是否通过ActRIIB发出信号。在这里，我们通过遗传学和生物化学研究证明，ActRIIB及其亚家族受体ActRIIA在轴向椎骨的模式形成中协同介导Gdf11信号，并且Gdf11与ActRIIA和ActRIIB都结合，并诱导Smad2磷酸化。此外，我们还表明，这两种受体在左右模式形成和前头结构发育过程中可以相互功能补偿，以介导另一种TGF-β配体Nodal的信号传导。
