Department of Genetics, Harvard Medical School, and Center for Systems Biology, Massachusetts General Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Curr Biol. 2010 Nov 23;20(22):1993-2002. doi: 10.1016/j.cub.2010.09.063. Epub 2010 Nov 4.
The vertebrate limb is a classical model for understanding patterning of three-dimensional structures during embryonic development. Although decades of research have elucidated the tissue and molecular interactions within the limb bud required for patterning and morphogenesis of the limb, the cellular and molecular events that shape the limb bud itself have remained largely unknown.
We show that the mesenchymal cells of the early limb bud are not disorganized within the ectoderm as previously thought but are instead highly organized and polarized. Using time-lapse video microscopy, we demonstrate that cells move and divide according to this orientation. The combination of oriented cell divisions and movements drives the proximal-distal elongation of the limb bud necessary to set the stage for subsequent morphogenesis. These cellular events are regulated by the combined activities of the WNT and FGF pathways. We show that WNT5A/JNK is necessary for the proper orientation of cell movements and cell division. In contrast, the FGF/MAPK signaling pathway, emanating from the apical ectodermal ridge, does not regulate cell orientation in the limb bud but instead establishes a gradient of cell velocity enabling continuous rearrangement of the cells at the distal tip of the limb.
Together, these data shed light on the cellular basis of vertebrate limb bud morphogenesis and uncover new layers to the sequential signaling pathways acting during vertebrate limb development.
脊椎动物肢体是理解胚胎发育过程中三维结构模式形成的经典模型。尽管几十年来的研究已经阐明了肢体芽中组织和分子相互作用对于肢体的模式形成和形态发生所必需的，但对于塑造肢体芽本身的细胞和分子事件仍然知之甚少。
我们表明，早期肢体芽的间质细胞不像以前认为的那样在表皮内没有组织紊乱，而是高度组织化和极化。通过延时视频显微镜，我们证明细胞根据这个方向移动和分裂。定向细胞分裂和运动的组合驱动了肢体芽的近-远伸长，这是为随后的形态发生奠定基础所必需的。这些细胞事件受 WNT 和 FGF 途径的联合活性调节。我们表明，WNT5A/JNK 对于细胞运动和细胞分裂的正确定向是必需的。相比之下，来自顶端外胚层嵴的 FGF/MAPK 信号通路并不调节肢体芽中的细胞定向，而是建立了细胞速度的梯度，使肢体远端尖端的细胞能够不断重新排列。
这些数据揭示了脊椎动物肢体芽形态发生的细胞基础，并揭示了在脊椎动物肢体发育过程中作用的连续信号通路的新层次。
