Smad4 is required to regulate the fate of cranial neural crest cells
Smad4 is required to regulate the fate of cranial neural crest cells
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DOI：
10.1016/j.ydbio.2007.09.050
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发表时间：
2007-12-01
影响因子：
2.7
通讯作者：
Chai, Yang
中科院分区：
文献类型：
--
作者：
Ko, Seung O.;Chung, Il Hyuk;Chai, Yang
Smad 4是TGF-β/BMP信号的中心介导因子，其参与调节颅神经嵴（CNC）细胞的形成、迁移、增殖和命运决定。目前尚不清楚TGF-β/BMP信号是否利用Smad依赖性或非依赖性途径来控制CNC细胞的发育。为了研究Smad 4在调节CNC细胞中的功能意义，我们产生了具有Smad 4基因的神经嵴特异性失活的小鼠。我们的研究表明，Smad 4是不需要的CNC细胞的迁移，但需要在神经嵴细胞的心脏流出道的发展。Smad 4在牙齿发育的早期阶段在CNC衍生的外生间充质中介导BMP信号传导是必不可少的，因为神经嵴衍生的细胞中Smad 4的条件性失活导致切牙和磨牙发育在牙板阶段被阻止。此外，Smad介导的TGF-β/BMP信号转导控制第一鳃弓内口/背口和近端/远端结构域的同源框基因模式。在细胞水平上，Smad 4介导的下游靶基因是第一鳃弓近端结构域CNC细胞存活所必需的。Smad 4突变小鼠显示第一鳃弓发育不全和中线融合缺陷。两者合计，我们的数据表明，TGF-β/BMP信号依赖于Smad依赖的途径，在外胚间充质介导的上皮间充质的相互作用，控制颅面器官发生。(c)2007年爱思唯尔公司All rights reserved.
Smad4 is the central mediator for TGF-beta/BMP signals, which are involved in regulating cranial neural crest (CNC) cell fort-nation, migration, proliferation and fate determination. It is unclear whether TGF-beta/BMP signals utilize Smad-dependent or -independent pathways to control the development of CNC cells. To investigate the functional significance of Smad4 in regulating CNC cells, we generated mice with neural crest specific inactivation of the Smad4 gene. Our study shows that Smad4 is not required for the migration of CNC cells, but is required in neural crest cells for the development of the cardiac outflow tract. Smad4 is essential in mediating BMP signaling in the CNC-derived ectomesenchyme during early stages of tooth development because conditional inactivation of Smad4 in neural crest derived cells results in incisor and molar development arrested at the dental lamina stage. Furthermore, Smad-mediated TGF-beta/BMP signaling controls the homeobox gene patterning of oral/aboral and proximal/distal domains within the first branchial arch. At the cellular level, a Smad4-mediated downstream target gene(s) is required for the survival of CNC cells in the proximal domain of the first branchial arch. Smad4 mutant mice show underdevelopment of the first branchial arch and midline fusion defects. Taken together, our data show that TGF-beta/BMP signals rely on Smad-dependent pathways in the ectomesenchyme to mediate epithelial-mesenchymal interactions that control craniofacial organogenesis. (c) 2007 Elsevier Inc. All rights reserved.