Wnt signaling in estrogen-induced lactotroph proliferation
Wnt signaling in estrogen-induced lactotroph proliferation
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DOI：
10.1242/jcs.078642
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发表时间：
2011-02-15
影响因子：
4
通讯作者：
Davis, Julian R. E.
中科院分区：
文献类型：
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作者：
Giles, Adam;Madec, Frederic;Davis, Julian R. E.
催乳素瘤是人类最常见的功能性垂体腺瘤，但促乳素细胞增殖的控制尚不清楚。在这里，利用基因芯片分析，我们发现雌激素治疗增加了成年Fischer大鼠脑下垂体组织中Wnt4的表达。双重免疫荧光分析表明，WNT4的表达不仅限于促乳素细胞，而且在所有类型的垂体前叶细胞中都有表达。雌二醇诱导生长激素GH3细胞的增殖，与WNT4基因和蛋白的诱导平行。Tcf和Lef依赖转录的报告基因分析表明，在Wnt条件培养液刺激下，GH3细胞中典型的Wnt途径没有激活，也没有结构性活性突变体β-catenin的共同表达。β-连环素在GH3细胞和正常大鼠垂体前叶细胞中的表达仅局限于细胞膜，不受雌二醇的影响，在所测试的任何条件下均未检测到核β-连环素的表达。我们首次证明了WNT4通过抑制GH3细胞中的钙振荡来影响垂体中的非典型信号，尽管下游的影响尚不清楚。综上所述，WNT4在成年脑下垂体中表达，并且其表达被雌激素暴露所增加，这表明其参与成人组织可塑性可能涉及依赖于β-连环蛋白的信号通路。
Prolactinomas are the most common type of functioning pituitary adenoma in humans, but the control of lactotroph proliferation remains unclear. Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue. Dual immunofluorescence analysis revealed that Wnt4 expression was not confined to lactotrophs, but that it was expressed in all anterior pituitary cell types. Estradiol induced proliferation in the somatolactotroph GH3 cell line, in parallel with Wnt4 mRNA and protein induction. A reporter gene assay for TCF- and LEF-dependent transcription revealed that there was no activation of the canonical Wnt pathway in GH3 cells upon stimulation with Wnt-conditioned culture medium or coexpression of constitutively active mutant beta-catenin. Expression of beta-catenin in both GH3 cells and normal rat anterior pituitary cells was restricted to the cell membrane and was unaltered by treatment with estradiol, with no nuclear beta-catenin being detected under any of the conditions tested. We show for the first time that Wnt4 affects non-canonical signaling in the pituitary by inhibiting Ca2+ oscillations in GH3 cells, although the downstream effects are as yet unknown. In summary, Wnt4 is expressed in the adult pituitary gland, and its expression is increased by estrogen exposure, suggesting that its involvement in adult tissue plasticity is likely to involve beta-cateninin-dependent signaling pathways.