Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a
Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a
复制标题
DOI：
10.1073/pnas.1534900100
复制
发表时间：
2003-10-28
影响因子：
11.1
通讯作者：
Arenas, E
中科院分区：
文献类型：
--
作者：
Castelo-Branco, GA;Wagner, J;Arenas, E
wits是一个糖蛋白家族，它调节细胞增殖、命运决定和分化。在我们的研究中，我们检测了wnt对腹侧中脑（VM）多巴胺能（DA）神经元发育的贡献。我们的研究结果表明，β -连环蛋白在DA前体细胞中表达，β -连环蛋白信号在这些细胞中发生，正如TOPGAL [Tcf最佳启动子-半乳糖苷酶]报告小鼠所评估的那样。我们还发现Wnt-1、-3a和-5a的表达在发育过程中受到差异调节，部分纯化的Writs对VM发育有明显的调节作用。Wnt-3a促进了表达孤儿核受体相关因子1 （Nurr1）的前体细胞的增殖，但没有增加酪氨酸羟化酶阳性神经元的数量。相反，Wnt-1和-5a通过两种不同的机制增加了大鼠胚胎14.5天前体细胞培养中脑DA神经元的数量。Wnt-1主要增加Nurr1+前体、上调细胞周期蛋白D1和D3、下调p27和p57 mrna的增殖。相比之下，Wnt-5a主要增加了获得神经元DA表型的Nurr1+前体的比例，上调了Ptx3和c-ret mRNA的表达。此外，Frizzled-8（一种Wnt抑制剂）的可溶性半胱氨酸富结构域阻断了内源性Writs以及Wnt-1和-5a对前体细胞增殖和DA表型获得的影响。这些研究结果表明，wnt是VM神经发生过程中DA前体增殖和分化的关键调节因子，不同的wnt具有特定和独特的活性谱。
The Writs are a family,of glycoproteins that regulate cell proliferation, fate decisions, and differentiation. In our study, we examined the contribution of Wnts to the development of ventral midbrain (VM) dopaminergic (DA) neurons. Our results show that beta-catenin is expressed in DA precursor cells and that beta-catenin signaling takes place in these cells, as assessed in TOPGAL [Tcf optimal-promoter beta-galactosidase] reporter mice. We also found that Wnt-1, -3a, and -5a expression is differentially regulated during development and that partially purified Writs distinctively regulate VM development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons. Instead, Wnt-1 and -5a increased the number of rat midbrain DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1+ precursors, up-regulated cyclins D1 and D3, and down-regulated p27 and p57 mRNAs. In contrast, Wnt-5a primarily- increased the proportion of Nurr1+ precursors that acquired a neuronal DA phenotype and up-regulated the expression of Ptx3 and c-ret mRNA. Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Writs and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and that different Writs have specific and unique activity profiles.