Kogata Naoko, Oliemuller Erik, Wansbury Olivia, Howard Beatrice A
Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research , London, United Kingdom .
Stem Cells Dev. 2014 Nov 15;23(22):2758-70. doi: 10.1089/scd.2014.0082. Epub 2014 Aug 11.
Mutation of Neuregulin-3 (Nrg3) results in defective embryonic mammary gland development. Here, we investigate functions of Nrg3 signaling in embryonic mammary morphogenesis. Nrg3 regulates the distribution of epithelial progenitor cells within the presumptive mammary-forming region during early mammary morphogenesis. Basal and suprabasal epithelial cells are significantly smaller within the hypoplastic mammary primordium (MP) that forms in Nrg3 mutants, indicative of failure to acquire mammary epithelial cell (MEC) morphological phenotype. Activation of Erbb4 JM-a CYT-1, an Erbb4 isoform expressed in the developing MP, leads to MEC spreading and migration. Nrg3 promotes the accumulation of epithelial progenitor cells at the MP site in embryo explant cultures. Our results implicate Nrg3 signaling in mediating key events of mammary mesenchyme specification, including mesenchymal condensation, mitosis, and induction of mammary marker expression. Taken together, our results show Nrg3 has a major role in conferring specification of the mammary phenotype to both epithelial and mesenchymal progenitor cells.
神经调节蛋白-3（Nrg3）的突变会导致胚胎期乳腺发育缺陷。在此，我们研究Nrg3信号在胚胎期乳腺形态发生中的功能。在早期乳腺形态发生过程中，Nrg3调节上皮祖细胞在假定的乳腺形成区域内的分布。在Nrg3突变体中形成的发育不全的乳腺原基（MP）内，基底和基底上层上皮细胞显著更小，这表明未能获得乳腺上皮细胞（MEC）的形态学表型。激活Erbb4 JM-a CYT-1（一种在发育中的MP中表达的Erbb4异构体）会导致MEC铺展和迁移。在胚胎外植体培养中，Nrg3促进上皮祖细胞在MP位点的积累。我们的结果表明Nrg3信号参与介导乳腺间充质特化的关键事件，包括间充质凝聚、有丝分裂以及乳腺标志物表达的诱导。综上所述，我们的结果表明Nrg3在赋予上皮和间充质祖细胞乳腺表型特化方面起主要作用。
