Xu Xun, Han Jun, Ito Yoshihiro, Bringas Pablo, Deng Chuxia, Chai Yang
Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
Dev Cell. 2008 Aug;15(2):322-9. doi: 10.1016/j.devcel.2008.06.004.
Smad4 is a central intracellular effector of TGF-beta signaling. Smad-independent TGF-beta pathways, such as those mediated by p38 MAPK, have been identified in cell culture systems, but their in vivo functional mechanisms remain unclear. In this study, we investigated the role of TGF-beta signaling in tooth and palate development and noted that conditional inactivation of Smad4 in oral epithelium results in much milder phenotypes than those seen with the corresponding receptor mutants, Bmpr1a and Tgfbr2, respectively. Perturbed p38 function in these tissues likewise has no effect by itself; however, when both Smad4 and p38 functions are compromised, dramatic recapitulation of the receptor mutant phenotypes results. Thus, our study demonstrates that p38 and Smad4 are functionally redundant in mediating TGF-beta signaling in diverse contexts during embryonic organogenesis. The ability of epithelium to utilize both pathways illustrates the complicated nature of TGF-beta signaling mechanisms in development and disease.
Smad4是转化生长因子β（TGF-β）信号传导的核心细胞内效应因子。在细胞培养系统中已鉴定出不依赖Smad的TGF-β信号通路，如由p38丝裂原活化蛋白激酶（p38 MAPK）介导的通路，但其体内功能机制仍不清楚。在本研究中，我们研究了TGF-β信号在牙齿和腭部发育中的作用，并注意到口腔上皮中Smad4的条件性失活所导致的表型比相应受体突变体Bmpr1a和Tgfbr2所导致的表型要温和得多。这些组织中p38功能受到干扰本身同样没有影响；然而，当Smad4和p38的功能都受到损害时，会显著重现受体突变体表型。因此，我们的研究表明，在胚胎器官发生过程中的不同情况下，p38和Smad4在介导TGF-β信号传导方面功能冗余。上皮细胞利用这两种信号通路的能力说明了TGF-β信号传导机制在发育和疾病中的复杂性。
