Modulation of noncanonical TGF-β signaling prevents cleft palate in Tgfbr2 mutant mice
Modulation of noncanonical TGF-β signaling prevents cleft palate in Tgfbr2 mutant mice
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DOI：
10.1172/jci61498
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Chai, Yang
中科院分区：
文献类型：
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作者：
Iwata, Jun-ichi;Hacia, Joseph G.;Chai, Yang
TGF-β受体I型（TGFBR 1）或TGF-β受体II型（TGFBR 2）突变的患者，如Loeys-Dietz综合征患者，具有颅面缺陷和TGF-β信号升高的迹象。类似地，TGF-β受体基因家族成员的突变会导致小鼠的颅面畸形，如腭裂。然而，目前尚不清楚TGF-β配体是否能够在Tgfbr 2突变小鼠中引发信号。在这里，我们发现，小鼠颅神经嵴细胞中Tgfbr 2的缺失导致TGF-β 2和TGF-β受体III型（T β RIII）的表达升高; T β RI/T β RIII介导的、SMAD非依赖性的TRAF 6/TAK 1/p38信号通路的激活;以及腭间充质中细胞增殖缺陷。引人注目的是，Tgfb 2、Tgfbr 1（也称为Alk 5）或Tak 1单倍不足破坏了Tgfbr 2突变小鼠中T β RI/T β RIII介导的信号传导并挽救了颅面畸形，表明这种非经典TGF-β信号传导途径的激活是Tgfbr 2突变小鼠颅面畸形的原因。因此，TGF-β信号转导的调节可能有利于预防先天性颅面出生缺陷。
Patients with mutations in either TGF-beta receptor type I (TGFBR1) or TGF-beta receptor type II (TGFBR2), such as those with Loeys-Dietz syndrome, have craniofacial defects and signs of elevated TGF-beta signaling. Similarly, mutations in TGF-beta receptor gene family members cause craniofacial deformities, such as cleft palate, in mice. However, it is unknown whether TGF-beta ligands are able to elicit signals in Tgfbr2 mutant mice. Here, we show that loss of Tgfbr2 in mouse cranial neural crest cells results in elevated expression of TGF-beta 2 and TGF-beta receptor type III (T beta RIII); activation of a T beta RI/T beta RIII-mediated, SMAD-independent, TRAF6/TAK1/p38 signaling pathway; and defective cell proliferation in the palatal mesenchyme. Strikingly, Tgfb2, Tgfbr1 (also known as Alk5), or Tak1 haploinsufficiency disrupted T beta RI/T beta RIII-mediated signaling and rescued craniofacial deformities in Tgfbr2 mutant mice, indicating that activation of this noncanonical TGF-beta signaling pathway was responsible for craniofacial malformations in Tgfbr2 mutant mice. Thus, modulation of TGF-beta signaling may be beneficial for the prevention of congenital craniofacial birth defects.