Jamora Colin, DasGupta Ramanuj, Kocieniewski Pawel, Fuchs Elaine
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10021, USA.
Nature. 2003 Mar 20;422(6929):317-22. doi: 10.1038/nature01458.
The morphogenesis of organs as diverse as lungs, teeth and hair follicles is initiated by a downgrowth from a layer of epithelial stem cells. During follicular morphogenesis, stem cells form this bud structure by changing their polarity and cell-cell contacts. Here we show that this process is achieved through simultaneous receipt of two external signals: a Wnt protein to stabilize beta-catenin, and a bone morphogenetic protein (BMP) inhibitor to produce Lef1. Beta-catenin then binds to, and activates, Lef1 transcription complexes that appear to act uncharacteristically by downregulating the gene encoding E-cadherin, an important component of polarity and intercellular adhesion. When either signal is missing, functional Lef1 complexes are not made, and E-cadherin downregulation and follicle morphogenesis are impaired. In Drosophila, E-cadherin can influence the plane of cell division and cytoskeletal dynamics. Consistent with this notion, we show that forced elevation of E-cadherin levels block invagination and follicle production. Our findings reveal an intricate molecular programme that links two extracellular signalling pathways to the formation of a nuclear transcription factor that acts on target genes to remodel cellular junctions and permit follicle formation.
诸如肺、牙齿和毛囊等多种器官的形态发生是由一层上皮干细胞向下生长引发的。在毛囊形态发生过程中，干细胞通过改变其极性和细胞间接触形成这种芽状结构。我们在此表明，这一过程是通过同时接收两种外部信号实现的：一种Wnt蛋白来稳定β-连环蛋白，以及一种骨形态发生蛋白（BMP）抑制剂来产生Lef1。然后，β-连环蛋白结合并激活Lef1转录复合物，该复合物似乎通过下调编码E-钙黏蛋白（极性和细胞间黏附的重要组成部分）的基因，以一种不同寻常的方式发挥作用。当任何一种信号缺失时，功能性Lef1复合物就无法形成，E-钙黏蛋白的下调和毛囊形态发生就会受损。在果蝇中，E-钙黏蛋白可以影响细胞分裂平面和细胞骨架动力学。与此观点一致，我们表明，强制提高E-钙黏蛋白水平会阻止内陷和毛囊生成。我们的研究结果揭示了一个复杂的分子程序，该程序将两条细胞外信号通路与一种核转录因子的形成联系起来，这种核转录因子作用于靶基因以重塑细胞连接并允许毛囊形成。
