ten Berge Derk, Brugmann Samantha A, Helms Jill A, Nusse Roel
Howard Hughes Medical Institute, Department of Developmental Biology, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Development. 2008 Oct;135(19):3247-57. doi: 10.1242/dev.023176.
A fundamental question in developmental biology is how does an undifferentiated field of cells acquire spatial pattern and undergo coordinated differentiation? The development of the vertebrate limb is an important paradigm for understanding these processes. The skeletal and connective tissues of the developing limb all derive from a population of multipotent progenitor cells located in its distal tip. During limb outgrowth, these progenitors segregate into a chondrogenic lineage, located in the center of the limb bud, and soft connective tissue lineages located in its periphery. We report that the interplay of two families of signaling proteins, fibroblast growth factors (FGFs) and Wnts, coordinate the growth of the multipotent progenitor cells with their simultaneous segregation into these lineages. FGF and Wnt signals act together to synergistically promote proliferation while maintaining the cells in an undifferentiated, multipotent state, but act separately to determine cell lineage specification. Withdrawal of both signals results in cell cycle withdrawal and chondrogenic differentiation. Continued exposure to Wnt, however, maintains proliferation and re-specifies the cells towards the soft connective tissue lineages. We have identified target genes that are synergistically regulated by Wnts and FGFs, and show how these factors actively suppress differentiation and promote growth. Finally, we show how the spatial restriction of Wnt and FGF signals to the limb ectoderm, and to a specialized region of it, the apical ectodermal ridge, controls the distribution of cell behaviors within the growing limb, and guides the proper spatial organization of the differentiating tissues.
发育生物学中的一个基本问题是，一个未分化的细胞群如何获得空间模式并经历协调分化？脊椎动物肢体的发育是理解这些过程的一个重要范例。发育中肢体的骨骼和结缔组织均源自位于其远端的一群多能祖细胞。在肢体生长过程中，这些祖细胞分离为位于肢芽中心的软骨生成谱系和位于其周边的软结缔组织谱系。我们报告称，两类信号蛋白，即成纤维细胞生长因子（FGFs）和Wnts，之间的相互作用协调了多能祖细胞的生长以及它们同时向这些谱系的分离。FGF和Wnt信号共同作用以协同促进增殖，同时使细胞维持在未分化的多能状态，但它们分别作用以决定细胞谱系特化。两种信号的撤除导致细胞周期退出和软骨生成分化。然而，持续暴露于Wnt会维持增殖并使细胞重新特化为软结缔组织谱系。我们已经鉴定出受Wnts和FGFs协同调控的靶基因，并展示了这些因子如何积极抑制分化并促进生长。最后，我们展示了Wnt和FGF信号在肢体外胚层以及其一个特殊区域——顶端外胚层嵴中的空间限制，如何控制生长中肢体内部细胞行为的分布，并引导分化组织的正确空间组织。
