Barna Maria, Pandolfi Pier Paolo, Niswander Lee
Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
Nature. 2005 Jul 14;436(7048):277-81. doi: 10.1038/nature03801.
The vertebrate limb initially develops as a bud of mesenchymal cells that subsequently aggregate in a proximal to distal (P-D) sequence to give rise to cartilage condensations that prefigure all limb skeletal components. Of the three cardinal limb axes, the mechanisms that lead to establishment and patterning of skeletal elements along the P-D axis are the least understood. Here we identify a genetic interaction between Gli3 (GLI-Kruppel family member 3) and Plzf (promyelocytic leukaemia zinc finger, also known as Zbtb16 and Zfp145), which is required specifically at very early stages of limb development for all proximal cartilage condensations in the hindlimb (femur, tibia, fibula). Notably, distal condensations comprising the foot are relatively unperturbed in Gli3(-/-);Plzf(-/-) mouse embryos. We demonstrate that the cooperative activity of Gli3 and Plzf establishes the correct temporal and spatial distribution of chondrocyte progenitors in the proximal limb-bud independently of known P-D patterning markers and overall limb-bud size. Moreover, the limb defects in Gli3(-/-);Plzf(-/-) embryos correlate with the transient death of a specific subset of proximal mesenchymal cells that express bone morphogenetic protein receptor, type 1B (Bmpr1b) at the onset of limb development. These findings suggest that the development of proximal and distal skeletal elements is distinctly regulated early during limb-bud formation. The initial division of the vertebrate limb into two distinct molecular domains is consistent with fossil evidence indicating that the upper and lower extremities of the limb have different evolutionary origins.
脊椎动物的肢体最初是作为间充质细胞芽发育而来的，这些间充质细胞随后以近端到远端（P-D）的顺序聚集，形成软骨凝聚物，这些凝聚物预示着所有肢体骨骼成分。在肢体的三个主要轴中，导致沿P-D轴建立和形成骨骼元素的机制了解最少。在这里，我们确定了Gli3（GLI-Kruppel家族成员3）和Plzf（早幼粒细胞白血病锌指，也称为Zbtb16和Zfp145）之间的遗传相互作用，Plzf在肢体发育的非常早期阶段对于后肢（股骨、胫骨、腓骨）的所有近端软骨凝聚物是特异性必需的。值得注意的是，在Gli3(-/-);Plzf(-/-)小鼠胚胎中，构成足部的远端凝聚物相对未受干扰。我们证明，Gli3和Plzf的协同活性独立于已知的P-D模式标记和整体肢芽大小，在近端肢芽中建立了软骨细胞祖细胞的正确时空分布。此外，Gli3(-/-);Plzf(-/-)胚胎中的肢体缺陷与在肢体发育开始时表达骨形态发生蛋白受体1B（Bmpr1b）的特定近端间充质细胞亚群的短暂死亡相关。这些发现表明，近端和远端骨骼元素的发育在肢芽形成早期受到明显不同的调节。脊椎动物肢体最初分为两个不同分子域，这与化石证据一致，表明肢体的上肢和下肢有不同的进化起源。
