Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb
Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb
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DOI：
10.1006/dbio.2000.9981
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发表时间：
2001-01-15
影响因子：
2.7
通讯作者：
Rosen, V
中科院分区：
文献类型：
--
作者：
Gamer, LW;Cox, KA;Rosen, V
GDF11是转化生长因子-β基因超家族中的一个新成员，在小鼠胚胎发育过程中调节轴骨的前/后模式。GDF11基因缺失的小鼠表现出骨骼异常，这似乎代表了椎骨的前同源同源转化，与原始条纹、分裂前中胚层和尾芽中GDF11的高水平表达一致。然而，尽管在整个发育过程中，Gdf11在肢体中都有强烈的表达，但这种结构在基因敲除小鼠中似乎没有受到影响。为了了解Gdf11表达与Gdf11功能的这种二分性，我们鉴定了鸡Gdf11基因，并研究了它在肢体形成中的作用。在早期的肢芽中，Gdf11转录本在远端外胚层下的中胚层中检测到，位于与进展区重叠的区域。在这些阶段，Gdf11被排除在中央核心间充质中，在那里将形成软骨前凝聚。在发育后期，Gdf11继续在最远端的间质中表达，也可以在更近端的形成骨架元素之间检测到。当在GDF11蛋白中孵化的珠子被植入早期翼芽时，GDF11会导致肢体严重截断，影响软骨元素和肌肉。肢体缩短似乎是抑制软骨生成和肌肉生成的结果，我们用体外微量分析证实了GDF11对肌源性和软骨源性细胞分化的负面影响。骨骼模式的分子标记分析表明，GDF11诱导了Herd-Il和Hoxd-13的异位表达，而不诱导Hoxa-11、Hoxa-13或MSx基因的异位表达。这些数据表明，GDF11可能参与了肢体发育过程中群体基因的晚期远端表达，过量的GDF11对这些HOX基因的错误调控可能会导致观察到的骨骼元素形状的一些变化。此外，GDF11还诱导了其自身拮抗剂Folistatin的表达，表明GFD11的活性可能受到负反馈机制的限制。我们在雏鸡身上的研究数据表明，Gdf11在鸟类肢体骨骼的形成和发育中发挥了作用。(C)2000年学术出版社。
GDF11, a new member of the TGF-P gene superfamily, regulates anterior/posterior patterning in the axial skeleton during mouse embryogenesis. Gdf11 null mice display skeletal abnormalities that appear to represent anterior homeotic transformations of vertebrae consistent with high levels of Gdf11 expression in the primitive streak, presomitic mesoderm, and tail bud. However, despite strong Gdf11 expression in the limb throughout development, this structure does not appear to be affected in the knockout mice. In order to understand this dichotomy of Gdf11 expression versus Gdf11 function, we identified the chicken Gdf11 gene and studied its role during limb formation. In the early limb bud, Gdf11 transcripts are detected in the subectodermal mesoderm at the distal tip, in a region overlapping the progress zone. At these stages, Gdf11 is excluded from the central core mesenchyme where precartilaginous condensations will form. Later in development, Gdf11 continues to be expressed in the distal most mesenchyme and can also be detected more proximally, in between the forming skeletal elements. When beads incubated in GDF11 protein were implanted into the early wing bud, GDF11 caused severe truncations of the limb that affected both the cartilage elements and the muscle. Limb shortening appeared to be the result of an inhibition of chondrogenesis and myogenesis and using an in vitro micromass assay, we confirmed the negative effects of GDF11 on both myogenic and chondrogenic cell differentiation. Analysis of molecular markers of skeletal patterning revealed that GDF11 induced ectopic expression of Herd-Il and Hoxd-13, but not of Hoxa-11, Hoxa-13, or the Msx genes. These data suggest that GDF11 may be involved in controlling the late distal expression of the Herd genes during limb development and that misregulation of these Hox genes by excess GDF11 may cause some of the observed alterations in skeletal element shape. In addition, GDF11 induced the expression of its own antagonist follistatin, indicating that the activity of GFD 11 may be limited by a negative feedback mechanism. The data from our studies in the chick suggest that Gdf11 plays a role in the formation and development of the avian limb skeleton. (C) 2000 Academic Press.