Hoodless P A, Tsukazaki T, Nishimatsu S, Attisano L, Wrana J L, Thomsen G H
Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario, M5S 1A8, Canada.
Dev Biol. 1999 Mar 15;207(2):364-79. doi: 10.1006/dbio.1998.9168.
Smads are central mediators of signal transduction for the TGFbeta superfamily. However, the precise functions of Smad-mediated signaling pathways in early development are unclear. Here we demonstrate a requirement for Smad2 signaling in dorsoanterior axis formation during Xenopus development. Using two point mutations of Smad2 previously identified in colorectal carcinomas, we show that Smad2 ushers Smad4 to the nucleus to form a transcriptional activation complex with the nuclear DNA-binding protein FAST-1 and that the mutant proteins interact normally with FAST-1 but fail to recruit Smad4 into the nucleus. This mechanism of inhibition specifically restricts the dominant-negative activity of these mutants to the activin/Vg1 signaling pathway without inhibiting BMPs. Furthermore, expression of these mutants in Xenopus animal caps inhibits but does not abolish activin and Vg1 induction of mesoderm and in the embryo results in a truncated dorsoanterior axis. These studies define a mechanism through which mutations in Smad2 may block TGFbeta-dependent signaling and suggest a critical role for inductive signaling mediated by the Smad2 pathway in Xenopus organizer function.
Smads是转化生长因子β（TGFβ）超家族信号转导的核心介质。然而，Smad介导的信号通路在早期发育中的精确功能尚不清楚。在此，我们证明了非洲爪蟾发育过程中背前轴形成需要Smad2信号。利用先前在结直肠癌中鉴定出的Smad2的两个点突变，我们发现Smad2将Smad4引导至细胞核，与核DNA结合蛋白FAST-1形成转录激活复合物，并且突变蛋白能正常与FAST-1相互作用，但无法将Smad4募集到细胞核中。这种抑制机制特异性地将这些突变体的显性负性活性限制在激活素/Vg1信号通路，而不抑制骨形态发生蛋白（BMP）。此外，这些突变体在非洲爪蟾动物帽中的表达抑制但并未消除激活素和Vg1诱导的中胚层，并且在胚胎中导致背前轴截断。这些研究确定了Smad2突变可能阻断TGFβ依赖性信号传导的机制，并提示Smad2途径介导的诱导信号在非洲爪蟾组织者功能中起关键作用。
