Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Dev Biol. 2010 Nov 1;347(1):195-203. doi: 10.1016/j.ydbio.2010.08.022. Epub 2010 Aug 27.
Mice deficient in growth differentiation factor 11 (GDF11) signaling display anterior transformation of axial vertebrae and truncation of caudal vertebrae. However, the in vivo molecular mechanisms by which GDF11 signaling regulates the development of the vertebral column have yet to be determined. We found that Gdf11 and Acvr2b mutants are sensitive to exogenous RA treatment on vertebral specification and caudal vertebral development. We show that diminished expression of Cyp26a1, a retinoic acid inactivating enzyme, and concomitant elevation of retinoic acid activity in the caudal region of Gdf11(-/-) embryos may account for this phenomenon. Reduced expression or function of Cyp26a1 enhanced anterior transformation of axial vertebrae in wild-type and Acvr2b mutants. Furthermore, a pan retinoic acid receptor antagonist (AGN193109) could lessen the anterior transformation phenotype and rescue the tail truncation phenotype of Gdf11(-/-) mice. Taken together, these results suggest that GDF11 signaling regulates development of caudal vertebrae and is involved in specification of axial vertebrae in part by maintaining Cyp26a1 expression, which represses retinoic acid activity in the caudal region of embryos during the somitogenesis stage.
生长分化因子 11（GDF11）信号缺失的小鼠表现出轴向脊椎的前向转化和尾部脊椎的截断。然而，GDF11 信号调节脊椎柱发育的体内分子机制尚未确定。我们发现 Gdf11 和 Acvr2b 突变体对脊椎指定和尾部脊椎发育的外源性 RA 处理敏感。我们表明，Cyp26a1 的表达减少，一种视黄酸失活酶，以及尾部区域 Gdf11(-/-) 胚胎中视黄酸活性的升高可能解释了这一现象。Cyp26a1 的表达减少或功能丧失增强了野生型和 Acvr2b 突变体的轴向脊椎的前向转化。此外，泛视黄酸受体拮抗剂（AGN193109）可以减轻 Gdf11(-/-) 小鼠的前向转化表型并挽救其尾部截断表型。总之，这些结果表明 GDF11 信号调节尾部脊椎的发育，并通过维持 Cyp26a1 的表达部分参与轴向脊椎的指定，从而在体节形成阶段抑制胚胎尾部区域的视黄酸活性。
