BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling
BMP signals control limb bud interdigital programmed cell death by regulating FGF signaling
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DOI：
10.1242/dev.001677
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发表时间：
2007-06-15
期刊：
影响因子：
4.6
通讯作者：
Lewandoski, Mark
中科院分区：
文献类型：
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作者：
Pajni-Underwood, Sangeeta;Wilson, Catherine P.;Lewandoski, Mark
在缺乏织带的脊椎动物四肢中，通过程序性细胞死亡（PCD）去除胚胎互间区域。建立的模型表明，骨形态发生蛋白（BMP）直接触发了这种PCD，尽管对此尚无直接遗传证据。另外，BMP可能通过调节成纤维细胞生长因子（FGF）间接影响PCD，后者充当细胞存活因子。在这里，我们将小鼠BMP受体基因BMPR1A灭活，专门在肢体芽顶外胚层（AER）中，这是FGF活性的来源。早期失活完全阻止了AER形成。然而，肢体芽启动后的灭活会导致两个AER-FGFS，FGF4和FGF8的上调，以及导致四肢织布的PCD的损失。为了确定过量的FGF信号传导是否抑制了这些BMPR1A突变体肢体中的互化PCD，我们对BMPR1A，FGF4和FGF8进行了双重和三重AER特异性灭活。由于FGF4表达升高，织带持续存在BMPR1A和FGF8的AER特异性灭活。 BMPR1A，FGF8和FGF4副本的灭活消除了织带。我们得出的结论是，在正常的胚胎发生过程中，BMP信号传导通过调节AER-FGFS来间接调节PCD，这充当了互化间隙的生存因子。
In vertebrate limbs that lack webbing, the embryonic interdigit region is removed by programmed cell death (PCD). Established models suggest that bone morphogenetic proteins (BMPs) directly trigger such PCD, although no direct genetic evidence exists for this. Alternatively, BMPs might indirectly affect PCD by regulating fibroblast growth factors (FGFs), which act as cell survival factors. Here, we inactivated the mouse BMP receptor gene Bmpr1a specifically in the limb bud apical ectodermal ridge (AER), a source of FGF activity. Early inactivation completely prevents AER formation. However, inactivation after limb bud initiation causes an upregulation of two AER-FGFs, Fgf4 and Fgf8, and a loss of interdigital PCD leading to webbed limbs. To determine whether excess FGF signaling inhibits interdigit PCD in these Bmpr1a mutant limbs, we performed double and triple AER-specific inactivations of Bmpr1a, Fgf4 and Fgf8. Webbing persists in AER-specific inactivations of Bmpr1a and Fgf8 owing to elevated Fgf4 expression. Inactivation of Bmpr1a, Fgf8 and one copy of Fgf4 eliminates webbing. We conclude that during normal embryogenesis, BMP signaling to the AER indirectly regulates interdigit PCD by regulating AER-FGFs, which act as survival factors for the interdigit mesenchyme.