Formation of Proximal and Anterior Limb Skeleton Requires Early Function of Irx3 and Irx5 and Is Negatively Regulated by Shh Signaling
Formation of Proximal and Anterior Limb Skeleton Requires Early Function of Irx3 and Irx5 and Is Negatively Regulated by Shh Signaling
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DOI：
10.1016/j.devcel.2014.03.001
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发表时间：
2014-04-28
影响因子：
11.8
通讯作者：
Hui, Chi-chung
中科院分区：
文献类型：
--
作者：
Li, Danyi;Sakuma, Rui;Hui, Chi-chung
肢体骨骼模式在很大程度上依赖于分级的Sonic Hedgehog(Shh)信号。作为一种形态生成和生长线索，Shh调节后肢成分的同一性，包括尺骨/腓骨和指骨2到5。相比之下，近端和前部结构，包括肱骨/股骨、桡骨/胫骨和指骨1，被认为是独立于Shh的，规范它们的机制尚不清楚。在这里，我们展示了近端和前肢骨骼的模式化包括两个阶段。IRX3和IRX5(IRX3/5)在起始肢芽中是必需的，以指定股骨、胫骨和指骨1的祖细胞。然而，当Shh信号减弱时，IRX3/5基因缺失的小鼠可以恢复这些骨骼元素，这表明Shh在起始后负向调节它们的形成。我们的数据提供了遗传学证据，支持早期指定和逐步确定前肢模式的概念。
Limb skeletal pattern relies heavily on graded Sonic hedgehog (Shh) signaling. As a morphogen and growth cue, Shh regulates identities of posterior limb elements, including the ulna/fibula and digits 2 through 5. In contrast, proximal and anterior structures, including the humerus/femur, radius/tibia, and digit 1, are regarded as Shh independent, and mechanisms governing their specification are unclear. Here, we show that patterning of the proximal and anterior limb skeleton involves two phases. Irx3 and Irx5 (Irx3/5) are essential in the initiating limb bud to specify progenitors of the femur, tibia, and digit 1. However, these skeletal elements can be restored in Irx3/5 null mice when Shh signaling is diminished, indicating that Shh negatively regulates their formation after initiation. Our data provide genetic evidence supporting the concept of early specification and progressive determination of anterior limb pattern.