Transcriptional program induced by Wnt protein in human fibroblasts suggests mechanisms for cell cooperativity in defining tissue microenvironments.
Transcriptional program induced by Wnt protein in human fibroblasts suggests mechanisms for cell cooperativity in defining tissue microenvironments.
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Wnt蛋白在人成纤维细胞中诱导的转录程序提出了定义组织微环境的细胞合作性的机制。
DOI：
10.1371/journal.pone.0000945
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发表时间：
2007-09-26
期刊：
影响因子：
3.7
通讯作者：
Brown, Patrick O.
中科院分区：
文献类型：
--
作者：
Klapholz-Brown, Zach;Walmsley, Graham G.;Nusse, Ysbrand M.;Nusse, Roel;Brown, Patrick O.
Wnt信号系统在干细胞的发育、自我更新和分化的调节、细胞极性、形态发生和癌症中起着关键作用。鉴于Wnt信号在这些过程中的多方面作用，其对构成上皮组织支架和基础结构的基质细胞的转录作用引起了极大的兴趣。为了开始研究这些作用，我们使用DNA微阵列来鉴定人肺成纤维细胞中Wnt通路的转录靶点。在培养物中用活性Wnt 3a蛋白处理细胞，并在4小时和24小时收获RNA。如免疫荧光所示，β-连环蛋白的核积累和AXIN 2的诱导表明成纤维细胞被编程为响应细胞外Wnt信号。除了几个已知的Wnt靶点外，我们还发现了许多新的Wnt诱导基因，包括许多编码调控蛋白的转录本。具有重要发育作用的转录因子，包括HOX基因，主导了早期转录反应。此外，我们发现了在Wnt信号通路中发挥直接作用的几个基因的差异表达，以及参与其他细胞信号通路的基因，包括成纤维细胞生长因子（FGF）和骨形态发生蛋白（BMP）信号。由Wnt 3a诱导最高的基因是GREMLIN 2，其编码分泌的BMP拮抗剂。GREMLIN 2的高表达表明Wnt信号在维持干细胞小生境中的新作用，由此Wnt信号诱导附近的成纤维细胞产生BMP拮抗剂，抑制干细胞在其微环境中的分化并促进其扩增。我们认为，Wnt诱导的局部基质细胞的基因表达程序的变化可能发挥重要作用，在建立专门的壁龛好客的自我更新的正常或恶性上皮干细胞在体内。
The Wnt signaling system plays key roles in development, regulation of stem cell self-renewal and differentiation, cell polarity, morphogenesis and cancer. Given the multifaceted roles of Wnt signaling in these processes, its transcriptional effects on the stromal cells that make up the scaffold and infrastructure of epithelial tissues are of great interest. To begin to investigate these effects, we used DNA microarrays to identify transcriptional targets of the Wnt pathway in human lung fibroblasts. Cells were treated with active Wnt3a protein in culture, and RNA was harvested at 4 hours and 24 hours. Nuclear accumulation of ß-Catenin, as shown by immunofluorescence, and induction of AXIN2 demonstrate that fibroblasts are programmed to respond to extracellular Wnt signals. In addition to several known Wnt targets, we found many new Wnt induced genes, including many transcripts encoding regulatory proteins. Transcription factors with important developmental roles, including HOX genes, dominated the early transcriptional response. Furthermore, we found differential expression of several genes that play direct roles in the Wnt signaling pathway, as well as genes involved in other cell signaling pathways including fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signaling. The gene most highly induced by Wnt3a was GREMLIN2, which encodes a secreted BMP antagonist. Elevated expression of GREMLIN2 suggests a new role for Wnt signals in the maintenance of stem cell niches, whereby Wnt signals induce nearby fibroblasts to produce a BMP antagonist, inhibiting differentiation and promoting expansion of stem cells in their microenvironment. We suggest that Wnt-induced changes in the gene expression program of local stromal cells may play an important role in the establishment of specialized niches hospitable to the self-renewal of normal or malignant epithelial stem cells in vivo.
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确定乳腺癌中基质特征的测定。
影响因子：
9.8
作者：
通讯作者：
--
影响因子：
--
作者：
Willert, Jennifer;Epping, Mirjam;Pollack, Jonathan R;Brown, Patrick O;Nusse, Roel
通讯作者：
Nusse, Roel
DOI：
10.1073/pnas.091062498
发表时间：
2001-04-24
影响因子：
11.1
作者：
Tusher, VG;Tibshirani, R;Chu, G
通讯作者：
Chu, G
DOI：
10.1152/ajplung.00221.2006
发表时间：
2007-03-01
影响因子：
4.9
作者：
Deimling, Julie;Thompson, Kate;Post, Martin
通讯作者：
Post, Martin
影响因子：
5.3
作者：
Fukuda, Shinji;Abematsu, Masahiko;Taga, Tetsuya
通讯作者：
Taga, Tetsuya