TGF-beta type I receptor Alk5 regulates tooth initiation and mandible patterning in a type II receptor-independent manner.
TGF-beta type I receptor Alk5 regulates tooth initiation and mandible patterning in a type II receptor-independent manner.
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DOI：
10.1016/j.ydbio.2008.03.045
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发表时间：
2008-08
影响因子：
2.7
通讯作者：
Hu Zhao;K. Oka;P. Bringas;V. Kaartinen;Y. Chai
中科院分区：
文献类型：
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作者：
Hu Zhao;K. Oka;P. Bringas;V. Kaartinen;Y. Chai
TGF-β超家族成员通过异聚体受体复合物发出信号以调节颅面发育。TGF-β II型受体似乎仅结合TGF-β，而TGF-β I型受体（ALK 5）也结合TGF-β以外的配体。我们以前的工作表明，小鼠神经嵴细胞中Tgfbr 2的条件性失活导致严重的颅面骨缺损。在本研究中，我们检测并比较了TGF-β II型受体（Wnt 1-Cre; Tgfbr 2fl/fl）和TGF-β I型受体/Alk 5（Wnt 1-Cre; Alk 5 fl/fl）条件性基因敲除小鼠的缺陷。神经嵴组织中Alk 5的缺失导致Tgfbr 2突变体中未观察到的表型，包括牙齿起始和发育延迟，早期下颌骨图案形成缺陷以及关键图案形成基因（包括Msx 1，Bmp 4，Bmp 2，Pax 9，Alx 4，Lhx 6/7和Gsc）的表达改变。Alk 5通过调节Gsc和其他基因在发育中的下颌骨近端背口区的表达来控制CNC细胞的存活。我们的结论是，ALK 5调节牙齿的启动和早期下颌骨图案通过独立的Tgfbr 2的途径。在牙齿和下颌骨发育过程中，Alk 5信号在调控CNC细胞的命运中具有内在要求。
TGF-β superfamily members signal through a heteromeric receptor complex to regulate craniofacial development. TGF-β type II receptor appears to bind only TGF-β, whereas TGF-β type I receptor (ALK5) also binds to ligands in addition to TGF-β. Our previous work has shown that conditional inactivation of Tgfbr2 in the neural crest cells of mice leads to severe craniofacial bone defects. In this study, we examine and compare the defects of TGF-β type II receptor (Wnt1-Cre;Tgfbr2fl/fl) and TGF-β type I receptor/Alk5 (Wnt1-Cre;Alk5fl/fl) conditional knockout mice. Loss of Alk5 in the neural crest tissue resulted in phenotypes not seen in the Tgfbr2 mutant, including delayed tooth initiation and development, defects in early mandible patterning and altered expression of key patterning genes including Msx1, Bmp4, Bmp2, Pax9, Alx4, Lhx6/7 and Gsc. Alk5 controls the survival of CNC cells by regulating expression of Gsc and other genes in the proximal aboral region of the developing mandible. We conclude that ALK5 regulates tooth initiation and early mandible patterning through a pathway independent of Tgfbr2. There is an intrinsic requirement for Alk5 signal in regulating the fate of CNC cells during tooth and mandible development.