Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON MS5 1A8, Canada.
Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
Dev Cell. 2014 Apr 28;29(2):233-40. doi: 10.1016/j.devcel.2014.03.001. Epub 2014 Apr 10.
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.
肢体骨骼模式在很大程度上依赖于分级 Sonic hedgehog（Shh）信号。作为一种形态发生素和生长线索，Shh 调节后肢元素的身份，包括尺骨/腓骨和第 2 至第 5 个手指。相比之下，近端和前侧结构，包括肱骨/股骨、桡骨/胫骨和第 1 个手指，被认为是 Shh 独立的，其指定的机制尚不清楚。在这里，我们表明近端和前侧肢体骨骼的模式形成涉及两个阶段。Irx3 和 Irx5（Irx3/5）在启动的肢芽中是必不可少的，以指定股骨、胫骨和第 1 个手指的祖细胞。然而，当 Shh 信号减弱时，Irx3/5 缺失小鼠中的这些骨骼元素可以被恢复，这表明 Shh 在启动后负调节它们的形成。我们的数据提供了遗传证据，支持了前肢模式早期指定和逐步确定的概念。
