Tgf-β3-induced palatal fusion is mediated by Alk-5/Smad pathway
Tgf-β3-induced palatal fusion is mediated by Alk-5/Smad pathway
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DOI：
10.1016/j.ydbio.2003.10.007
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发表时间：
2004-02-01
影响因子：
2.7
通讯作者：
Kaartinen, V
中科院分区：
文献类型：
--
作者：
Dudas, M;Nagy, A;Kaartinen, V
腭裂是人类最常见的出生缺陷之一，是由腭发育复杂的多步骤发育过程失败引起的。最近的研究表明，转化生长因子β 3（TGF-β 3）是成功的腭融合的绝对要求，无论是在小鼠和人类。然而，很少有人知道Tgf-beta3信号在这个过程中的机制。在这里，我们表明，推定的TGF-β I型受体，Alk-1，Alk-2，和Alk-5，都是内源性表达的腭上皮。Tgf-beta3（- / -）腭上皮中Alk-5的激活能够挽救腭融合，而野生型腭上皮中Alk-5的失活阻止腭融合。Alk-2的作用类似，但不太明显。在胚胎第14天（E14），通过激活Alk-5或Alk-2诱导的融合在腭的后部更强，而它们在E13.5的激活也恢复了前部融合，反映了体内腭成熟的自然前后方向。我们还表明，Smad 2是内源性激活的腭中线上皮缝（MES）在融合过程中。通过使用突变的Alk-5受体，这是一种活性激酶，但不能激活Smads，我们表明，激活Smad的非依赖性Tgf-beta3的反应是不足以诱导融合的货架缺乏Tgf-beta3。基于这些观察结果，我们得出结论，Smad 2依赖的ALK-5信号通路是主导的腭融合驱动的TGF-β 3。(C)2003年爱思唯尔公司All rights reserved.
Cleft palate is among the most common birth defects in humans, caused by a failure in the complex multistep developmental process of palatogenesis. It has been recently shown that transforming growth factor beta3 (Tgf-beta3) is an absolute requirement for successful palatal fusion, both in mice and humans. However, very little is known about the mechanisms of Tgf-beta3 signaling during this process. Here we show that putative Tgf-beta type I receptors, Alk-1, Alk-2, and Alk-5, are all endogenously expressed in the palatal epithelium. Activation of Alk-5 in the Tgf-beta3 ( - / -) palatal epithelium is able to rescue palatal fusion, whereas inactivation of Alk-5 in the wild-type palatal epithelium prevents palatal fusion. The effect of Alk-2 is similar, but less pronounced. The induction of fusion by activation of Alk-5 or Alk-2 is stronger in the posterior parts of the palates at the embryonic day 14 (E14), while their activation at E13.5 also restores anterior fusion, reflecting the natural anterior-posterior direction of palate maturation in vivo. We also show that Smad2 is endogenously activated in the palatal midline epithelial seam (MES) during the fusion process. By using a mutant Alk-5 receptor that is an active kinase but is unable to activate Smads, we show that activation of Smad-independent Tgf-beta3 responses is not sufficient to induce fusion of shelves deficient in Tgf-beta3. Based on these observations, we conclude that the Smad2-dependent Alk-5 signaling pathway is dominant in palatal fusion driven by Tgf-beta3. (C) 2003 Elsevier Inc. All rights reserved.