Bmp7 regulates branching morphogenesis of the lacrimal gland by promoting mesenchymal proliferation and condensation
Bmp7 regulates branching morphogenesis of the lacrimal gland by promoting mesenchymal proliferation and condensation
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DOI：
10.1242/dev.01285
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发表时间：
2004-09-01
期刊：
影响因子：
4.6
通讯作者：
Lang, RA
中科院分区：
文献类型：
--
作者：
Dean, C;Ito, M;Lang, RA
泪腺为研究分支形态发生过程中至关重要的上皮-间充质相互作用提供了一个很好的模型。在目前的研究中，我们发现骨形态发生蛋白7 （bone morphogenetic protein 7, Bmp7）在发育中的腺体中以一种复杂的模式表达，并在调节分支中发挥重要作用。在功能缺失分析中，我们发现bmp7缺失的小鼠泪腺分支数量明显减少，并且在腺体外植体培养中抑制Bmp活性具有非常相似的结果。与此一致的是，将整个腺体外植体暴露于重组Bmp7中会导致分支数量增加。为了确定腺体中哪些细胞对Bmp7有直接反应，我们测试了分离的间质和上皮细胞。我们发现，正如预期的那样，Bmp4可以抑制Fgf10刺激的离体上皮的芽扩展，但有趣的是，Bmp7没有明显的作用。然而，Bmp7确实能刺激间充质细胞产生不同的反应。这表现为促进细胞分裂和聚集体的形成，以及钙粘蛋白粘附分子、连接蛋白连接蛋白43和a-平滑肌肌动蛋白的上调。这些数据表明，在这个分支系统中，间质是Bmp7的主要目标，信号中心特征的间质凝聚的形成可能被Bmp7增强。基于Bmp7促进分支的活性，我们还提出了一个模型，表明表达Bmp7的头部间质的一个离散区域可能是决定腺体眶外叶位置的关键。
The lacrimal gland provides an excellent model with which to study the epithelial-mesenchymal interactions that are crucial to the process of branching morphogenesis. In the current study, we show that bone morphogenetic protein 7 (Bmp7) is expressed with a complex pattern in the developing gland and has an important role in regulating branching. In loss-of-function analyses, we find that Bmp7-null mice have distinctive reductions in lacrimal gland branch number, and that inhibition of Bmp activity in gland explant cultures has a very similar consequence. Consistent with this, exposure of whole-gland explants to recombinant Bmp7 results in increased branch number. In determining which cells of the gland respond directly to Bmp7, we have tested isolated mesenchyme and epithelium. We find that, as expected, Bmp4 can suppress bud extension in isolated epithelium stimulated by Fgf10, but interestingly, Bmp7 has no discernible effect. Bmp7 does, however, stimulate a distinct response in mesenchymal cells. This manifests as a promotion of cell division and formation of aggregates, and upregulation of cadherin adhesion molecules, the junctional protein connexin 43 and of a-smooth muscle actin. These data suggest that in this branching system, mesenchyme is the primary target of Bmp7 and that formation of mesenchymal condensations characteristic of signaling centers may be enhanced by Bmp7. Based on the activity of Bmp7 in promoting branching, we also propose a model suggesting that a discrete region of Bmp7-expressing head mesenchyme may be crucial in determining the location of the exorbital lobe of the gland.