Ito Yoshihiro, Bringas Pablo, Mogharei Ali, Zhao Jingsong, Deng Chuxia, Chai Yang
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA.
Dev Dyn. 2002 May;224(1):69-78. doi: 10.1002/dvdy.10088.
The proper development of Meckel's cartilage is critical for craniofacial skeletogenesis, because it serves as the primordium for the formation of mandible, malleus, incus, and sphenomandibular ligament. Cranial neural crest (CNC) cells contribute significantly to the formation of Meckel's cartilage. Members of the transforming growth factor beta (TGF-beta) family control the proliferation and differentiation of CNC cells during craniofacial skeletogenesis. TGF-beta signaling is transduced from the cell membrane to the nucleus by means of specific type I and type II receptors and phosphorylated Smad proteins. Here we demonstrate that application of TGF-beta promotes chondrogenesis by specifically increasing proliferation of CNC-derived chondrocytes and production of extracellular matrix. To understand the molecular regulation of TGF-beta signaling, we have examined the biological function of both TGF-beta receptor-regulated and inhibitory Smads during Meckel's cartilage development. The expression patterns of Smad2, 3, and 7 are identical to the ones of endogenous TGF-beta and its cognate receptors during Meckel's cartilage development, establishing the potential that these intracellular signaling Smads may regulate TGF-beta-mediated chondrogenesis. Functional haploinsufficiency of Smad2 delays TGF-beta-mediated Meckel's cartilage development. Overproduction of Smad7 severely inhibits Meckel's cartilage formation, indicating a negative feedback on TGF-beta signaling by inhibitory Smad is critical in orchestrating TGF-beta-mediated gene regulation during embryonic chondrogenesis. The effectiveness of TGF-beta signaling is highly sensitive to the level of Smad gene expression.
梅克尔软骨的正常发育对于颅面骨骼形成至关重要，因为它是下颌骨、锤骨、砧骨和蝶下颌韧带形成的原基。颅神经嵴（CNC）细胞对梅克尔软骨的形成有重要贡献。转化生长因子β（TGF-β）家族成员在颅面骨骼形成过程中控制CNC细胞的增殖和分化。TGF-β信号通过特定的I型和II型受体以及磷酸化的Smad蛋白从细胞膜传导至细胞核。在此我们证明，应用TGF-β可通过特异性增加CNC来源软骨细胞的增殖和细胞外基质的产生来促进软骨形成。为了解TGF-β信号的分子调控机制，我们研究了TGF-β受体调节型Smad和抑制型Smad在梅克尔软骨发育过程中的生物学功能。在梅克尔软骨发育过程中，Smad2、3和7的表达模式与内源性TGF-β及其同源受体的表达模式相同，这表明这些细胞内信号转导Smad可能调节TGF-β介导的软骨形成。Smad2的功能性单倍剂量不足会延迟TGF-β介导的梅克尔软骨发育。Smad7的过量表达会严重抑制梅克尔软骨的形成，这表明抑制型Smad对TGF-β信号的负反馈在胚胎软骨形成过程中协调TGF-β介导的基因调控方面至关重要。TGF-β信号的有效性对Smad基因表达水平高度敏感。
