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JBC:中科院水生所揭示斑马鱼Lzts2分子调控机制

摘要 : 中国科学院水生生物研究所崔宗斌研究员学科组在揭示斑马鱼Caveolin-1与β-Catenin相互作用调控经典Wnt通路活性(2010, Developmental Biology, 344:210-223)的基础上,深入研究了斑马鱼Lzts2的时空表达与调控、发育功能及其作用的分子机制。经研究发现:
经典Wnt信号通路细胞内的重要信号传导机制之一。该通路的激活可导致β-Catenin在细胞核内的积累,β-Catenin与TCF等转录因子相互作用,可调节多种下游基因的转录表达,并由此影响细胞的增殖、分化、凋亡和迁移。因此,该信号通路在脊椎动物早期胚胎发育和器官形成中起着重要作用,其活性的非正常变化与多种人体疾病密切相关。目前,尚待深入研究该通路在脊椎动物器官发育与形成中的作用及其细胞内信号传导的调控机制。 中国科学院水生生物研究所崔宗斌研究员学科组在揭示斑马鱼Caveolin-1与β-Catenin相互作用调控经典Wnt通路活性(2010, Developmental biology, 344:210-223)的基础上,深入研究了斑马鱼Lzts2的时空表达与调控、发育功能及其作用的分子机制。经研究发现:1)Lzts2可调控斑马鱼的背腹轴发育、胚胎细胞运动、重要器官前体细胞向中线汇聚和分化;2)Lzts2可与β-catenin直接相互作用,并促进β-Catenin向细胞质的转运和在细胞质中的降解,由此抑制经典Wnt信号通路的活性;3)通过突变分析精确定位了Lzts2与β-Catenin相互作用的氨基酸序列;4)提出Lzts2通过调节β-Catenin、非经典Wnt和Stat3信号通路活性,抑制胚胎细胞汇聚和延伸的模型。 这些研究结果为深入理解Wnt信号通路调控、发育功能、相关成体疾病分子机理,以及针对Lzts2设计小分子药物奠定了基础。 该研究得到国家重点基础研究计划、国家自然科学基金和“百人计划”择优项目的资助,主要由博士研究生李媛媛等完成。研究论文于11月4日在线发表在JBC杂志上。

原文摘要:
LZTS2 regulates embryonic Cell movements and dorsoventral patterning through interaction with and the export of nuclear β-Catenin in zebrafish Leucine zipper tumor suppressor 2 (Lzts2)functions in the development and progression of various tumors, but its activities in vertebrate embryogenesis remain unclear. Herein, we demonstrate that lzts2 transcripts are of maternal origin in zebrafish embryos. Activation of Bmp signaling upregulates zygotic expression of lzts2, while canonical Wnt signaling acts upstream of Bmp signaling to inhibit lzts2 expression. Abrogation of lzts2 expression by its specific MO enhanced gastrula convergence and extension (C&E) movements, dorsalized early embryos and inhibited specification of midline progenitors for pancreas, liver and heart.In contrast, ectopic expression of lzts2 led to the delay of C&E movements and midline convergence of organ progenitors, and resulted in a certain ratio of ventralized embryos. Mechanistically, Lzts2 regulates the migration of embryonic cells and dorsoventral patterning through its limitation of Wnt/β-catenin activity, since it physically interacts with β-catenin-1 and -2 and transports them out of the nucleus. In addition, both β-catenin-1 and -2 exhibit redundant functions in activation of Stat3 signaling and in induction of Wnt5/11 expression through inhibition of Bmp signaling and stimulation of Cyclops and Squint expression. Thus, Lzts2 regulates gastrula C&E movements, dorsoventral patterning, and midline convergence and specification of organ precursors through interaction with and the export of nuclear β-catenins in zebrafish.     作者:网友 点击:
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