Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
PLoS One. 2010 Jun 3;5(6):e10881. doi: 10.1371/journal.pone.0010881.
beta-Catenin is a multifunctional protein involved in both signalling by secreted factors of Wnt family and regulation of the cellular architecture. We show that beta-catenin stabilization in mouse midbrain-rhombomere 1 region leads to robust up-regulation of several Wnt signalling target genes, including Fgf8. Suggestive of direct transcriptional regulation of the Fgf8 gene, beta-catenin stabilization resulted in Fgf8 up-regulation also in other tissues, specifically in the ventral limb ectoderm. Interestingly, stabilization of beta-catenin rapidly caused down-regulation of the expression of Wnt1 itself, suggesting a negative feedback loop. The changes in signal molecule expression were concomitant with deregulation of anterior-posterior and dorso-ventral patterning. The transcriptional regulatory functions of beta-catenin were confirmed by beta-catenin loss-of-function experiments. Temporally controlled inactivation of beta-catenin revealed a cell-autonomous role for beta-catenin in the maintenance of cell-type specific gene expression in the progenitors of midbrain dopaminergic neurons. These results highlight the role of beta-catenin in establishment of neuroectodermal signalling centers, promoting region-specific gene expression and regulation of cell fate determination.
β-连环蛋白是一种多功能蛋白，参与 Wnt 家族分泌因子的信号传递和细胞结构的调节。我们发现，β-连环蛋白在小鼠中脑-菱脑 1 区的稳定化导致几个 Wnt 信号靶基因的强烈上调，包括 Fgf8。提示 Fgf8 基因的直接转录调控，β-连环蛋白的稳定化也导致其他组织中 Fgf8 的上调，特别是在腹侧肢体外胚层。有趣的是，β-连环蛋白的稳定化迅速导致 Wnt1 自身表达的下调，表明存在负反馈环。信号分子表达的变化伴随着前后轴和背腹轴模式的失调。β-连环蛋白的转录调控功能通过β-连环蛋白的功能丧失实验得到证实。β-连环蛋白的时间控制失活揭示了β-连环蛋白在维持中脑多巴胺能神经元祖细胞中细胞类型特异性基因表达中的细胞自主作用。这些结果突出了β-连环蛋白在建立神经外胚层信号中心、促进区域特异性基因表达和调节细胞命运决定中的作用。
