Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects
Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects
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DOI：
10.1242/dev.00708
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发表时间：
2003-11-01
期刊：
影响因子：
4.6
通讯作者：
Chai, Y
中科院分区：
文献类型：
--
作者：
Ito, Y;Yeo, JY;Chai, Y
腭裂和颅骨畸形是人类中一些最常见的先天性出生缺陷。先前的研究表明，TGFbeta 信号传导在颅骨发育过程中的腭融合和出生后颅缝闭合过程中调节内侧边缘上皮的命运。然而，尚不清楚 TGFbeta 信号传导在调节颅面发育过程中颅神经嵴 (CNC) 细胞的命运方面有何功能意义。我们发现，CNC 中 Tgfbr2 条件性基因消融的小鼠具有完全的次级腭裂、颅骨发育不全和其他具有完全表型外显率的颅骨缺陷。值得注意的是，TGFbeta 信号传导的破坏不会对 CNC 迁移产生不利影响。 Tgfbr2 突变小鼠的腭裂是由 CNC 衍生的腭间充质内的细胞增殖缺陷引起的。一旦腭架在体外紧密接触，突变腭架的中线上皮仍然具有介导腭融合的功能。我们的数据表明，TGFbeta IIR 在调节腭发育过程中 CNC 细胞的命运方面发挥着至关重要的细胞自主作用。在颅骨发育过程中，CNC 中 TGFbeta 信号传导的破坏会严重损害硬脑膜中的细胞增殖，从而导致颅骨发育不全。我们提供的体内证据表明，CNC 衍生的硬脑膜内的 TGFbeta 信号传导为 CNC 和中胚层衍生的颅骨发育提供了必要的诱导指令。本研究表明TGFbeta IIR在CNC的发育中发挥着重要作用，并为CNC发育异常的研究提供了模型。
Cleft palate and skull malformations represent some of the most frequent congenital birth defects in the human population. Previous studies have shown that TGFbeta signaling regulates the fate of the medial edge epithelium during palatal fusion and postnatal cranial suture closure during skull development. It is not understood, however, what the functional significance of TGFbeta signaling is in regulating the fate of cranial neural crest (CNC) cells during craniofacial development. We show that mice with Tgfbr2 conditional gene ablation in the CNC have complete cleft secondary palate, calvaria agenesis, and other skull defects with complete phenotype penetrance. Significantly, disruption of the TGFbeta signaling does not adversely affect CNC migration. Cleft palate in Tgfbr2 mutant mice results from a cell proliferation defect within the CNC-derived palatal mesenchyme. The midline epithelium of the mutant palatal shelf remains functionally competent to mediate palatal fusion once the palatal shelves are placed in close contact in vitro. Our data suggests that TGFbeta IIR plays a crucial, cell-autonomous role in regulating the fate of CNC cells during palatogenesis. During skull development, disruption of TGFbeta signaling in the CNC severely impairs cell proliferation in the dura mater, consequently resulting in calvaria agenesis. We provide in vivo evidence that TGFbeta signaling within the CNC-derived dura mater provides essential inductive instruction for both the CNC- and mesoderm-derived calvarial bone development. This study demonstrates that TGFbeta IIR plays an essential role in the development of the CNC and provides a model for the study of abnormal CNC development.