Ito Yoshihiro, Yeo Jae Yong, Chytil Anna, Han Jun, Bringas Pablo, Nakajima Akira, Shuler Charles F, Moses Harold L, Chai Yang
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Development. 2003 Nov;130(21):5269-80. doi: 10.1242/dev.00708.
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.
腭裂和颅骨畸形是人类中最常见的先天性出生缺陷。先前的研究表明，TGFβ信号通路在腭融合过程中调节内侧边缘上皮的命运，在颅骨发育过程中调节出生后颅缝闭合。然而，尚不清楚TGFβ信号通路在颅面发育过程中调节颅神经嵴（CNC）细胞命运的功能意义。我们发现，在CNC中进行Tgfbr2条件性基因敲除的小鼠具有完全性继发腭裂、颅骨发育不全和其他具有完全表型穿透性的颅骨缺陷。值得注意的是，TGFβ信号通路的破坏不会对CNC迁移产生不利影响。Tgfbr2突变小鼠的腭裂是由CNC来源的腭间充质内的细胞增殖缺陷引起的。一旦在体外将腭突紧密接触，突变腭突的中线上皮在功能上仍能介导腭融合。我们的数据表明，TGFβIIR在腭形成过程中调节CNC细胞命运方面发挥着关键的细胞自主作用。在颅骨发育过程中，CNC中TGFβ信号通路的破坏严重损害硬脑膜中的细胞增殖，从而导致颅骨发育不全。我们提供了体内证据，表明CNC来源的硬脑膜内的TGFβ信号通路为CNC和中胚层来源的颅骨发育提供了必要的诱导指令。这项研究表明，TGFβIIR在CNC的发育中起着至关重要的作用，并为研究异常CNC发育提供了一个模型。
