Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning
Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning
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DOI：
10.1038/nature06876
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发表时间：
2008-05-15
期刊：
影响因子：
64.8
通讯作者：
Martin, Gail R.
中科院分区：
文献类型：
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作者：
Mariani, Francesca V.;Ahn, Christina P.;Martin, Gail R.
半个世纪前，四足动物肢芽远端的顶端外胚层脊 (AER) 被证明可以产生沿近端-远端 (P-D) 轴发育所需的信号，但这些信号如何影响肢体模式仍存在很多争论 (1,2)。成纤维细胞生长因子 (FGF) 基因家族成员是关键的 AER 衍生信号 (3,4)，其中 Fgf4、Fgf8、Fgf9 和 Fgf17 在小鼠 AER 中特异性表达 (5)。在这里，我们证明缺乏 Fgf4、Fgf9 和 Fgf17 的小鼠四肢具有正常的骨骼模式，表明 AER-FGF 中的 Fgf8 足以维持正常的肢体形成。 Fgf8 单独失活会导致轻度骨骼表型 (6,7)；然而，当我们还去除其他 AER-FGF 基因的不同组合时，我们获得了意想不到的严重程度不断增加的骨骼表型，反映了每个 FGF 对总 AER-FGF 信号的贡献。对复合突变体肢芽的分析表明，除了维持细胞存活之外，AER-FGF 在早期肢芽发育过程中还调节 P-D 模式基因表达，提供了 AER-FGF 功能指定远端结构域的遗传证据，并挑战了长期以来的假设，即 AER-FGF 信号传导对于肢体模式是允许的而不是指导性的。我们讨论了如何将 P-D 模式的双信号模型与早期规范的概念相结合，以解释此处提供的遗传数据。
Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated(1,2). Fibroblast growth factor (FGF) gene family members are key AER-derived signals(3,4), with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER(5). Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype(6,7); however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning. We discuss how a two-signal model for P-D patterning can be integrated with the concept of early specification to explain the genetic data presented here.