Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development
Gli3 and Plzf cooperate in proximal limb patterning at early stages of limb development
复制标题
DOI：
10.1038/nature03801
复制
发表时间：
2005-07-14
期刊：
影响因子：
64.8
通讯作者：
Niswander, L
中科院分区：
文献类型：
--
作者：
Barna, M;Pandolfi, PP;Niswander, L
脊椎动物肢体最初发育为间充质细胞的芽，随后聚集在远端(P-D)近端(P-D)序列中，形成软骨凝结，预示着所有肢体骨骼组件(1)。在三个主要的肢轴中，导致骨骼元素沿P-D轴建立和形成的机制最不为人所知。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，这是后肢(股骨、胫骨、腓骨)所有近端软骨浓缩在肢体发育的非常早期阶段所必需的。值得注意的是，在Gli3(-/-)；PLZF(-/-)小鼠胚胎中，构成脚的远端凝结相对没有受到干扰。我们证明，Gli3和PLZF的协同活动建立了软骨细胞前体细胞在近侧肢芽中正确的时空分布，独立于已知的P-D模式标记和整体肢芽大小。此外，Gli3(-/-)；PLZF(-/-)胚胎的肢体缺陷与肢体发育初期表达骨形态发生蛋白受体1B型(Bmpr1b)的特定近端间充质细胞亚群的短暂死亡有关。这些发现表明，近端和远端骨骼元素的发育在肢芽形成的早期受到明显的调控。脊椎动物肢体最初分为两个不同的分子区域，这与化石证据相一致，表明肢体的上肢和下肢具有不同的进化起源(2)。
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(1). 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(2).