CTGF Mediates Smad-Dependent Transforming Growth Factor β Signaling To Regulate Mesenchymal Cell Proliferation during Palate Development
CTGF Mediates Smad-Dependent Transforming Growth Factor β Signaling To Regulate Mesenchymal Cell Proliferation during Palate Development
复制标题
DOI：
10.1128/mcb.00615-13
复制
发表时间：
2013-09-01
影响因子：
5.3
通讯作者：
Chai, Yang
中科院分区：
文献类型：
--
作者：
Parada, Carolina;Li, Jingyuan;Chai, Yang
转化生长因子β (tgf - β)信号在颅面发育，包括腭发生的调节中起着至关重要的作用。在这里，我们已经确定结缔组织生长因子（Ctgf）是腭裂发生中tgf - β信号通路的下游靶点。Ctgf在野生型胚胎中的表达模式表明它可能参与腭发育的关键过程。我们发现Ctgf在Wnt1-Cre中表达下调；Tgfbr2（fl/fl）和Osr2-Cre；Smad4 (fl / fl)。在Tgfbr2突变胚胎中，Ctgf表达下调与p38丝裂原活化蛋白激酶（MAPK）过度激活有关，而Smad4自身功能缺失导致Ctgf表达下调。我们还发现CTGF通过tgf - β信号调节自身表达。Osr2-Cre;Smad4（fl/fl）小鼠表现出与Tgfbr2突变小鼠相似的细胞增殖缺陷，以及腭裂。我们在Smad4突变腭中未检测到骨形态发生蛋白（BMP）下游靶点的改变，这表明细胞增殖的减少是由于tgf - β信号转导缺陷导致的。值得注意的是，外源CTGF能够挽救Tgfbr2和Smad4突变体腭的细胞增殖缺陷。总的来说，我们的数据表明，CTGF调节增殖是在腭发育过程中tgf - β信号传导的典型途径的中介。
Transforming growth factor beta (TGF-beta) signaling plays crucial functions in the regulation of craniofacial development, including palatogenesis. Here, we have identified connective tissue growth factor (Ctgf) as a downstream target of the TGF-beta signaling pathway in palatogenesis. The pattern of Ctgf expression in wild-type embryos suggests that it may be involved in key processes during palate development. We found that Ctgf expression is downregulated in both Wnt1-Cre; Tgfbr2(fl/fl) and Osr2-Cre;Smad4(fl/fl) palates. In Tgfbr2 mutant embryos, downregulation of Ctgf expression is associated with p38 mitogen-activated protein kinase (MAPK) overactivation, whereas loss of function of Smad4 itself leads to downregulation of Ctgf expression. We also found that CTGF regulates its own expression via TGF-beta signaling. Osr2-Cre; Smad4(fl/fl) mice exhibit a defect in cell proliferation similar to that of Tgfbr2 mutant mice, as well as cleft palate. We detected no alteration in bone morphogenetic protein (BMP) downstream targets in Smad4 mutant palates, suggesting that the reduction in cell proliferation is due to defective transduction of TGF-beta signaling via decreased Ctgf expression. Significantly, an exogenous source of CTGF was able to rescue the cell proliferation defect in both Tgfbr2 and Smad4 mutant palates. Collectively, our data suggest that CTGF regulates proliferation as a mediator of the canonical pathway of TGF-beta signaling during palatogenesis.