Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB
Ectodysplasin regulates hormone-independent mammary ductal morphogenesis via NF-κB
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DOI：
10.1073/pnas.1110627109
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发表时间：
2012-04-10
影响因子：
11.1
通讯作者：
Mikkola, Marja L.
中科院分区：
文献类型：
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作者：
Voutilainen, Maria;Lindfors, Paivi H.;Mikkola, Marja L.
乳腺导管的生长分为两个不同的阶段。第一轮分枝形态发生发生在胚胎发生期间，第二轮开始于青春期开始。目前，对控制导管扩张初始阶段的遗传网络知之甚少，与青春期发育不同，导管扩张独立于雌性小鼠的激素输入。在这里，我们确定NF-κ B B下游的肿瘤坏死因子样配体外胚层发育不良（埃达）作为一个独特的调节胚胎和青春期前导管形态发生。Eda缺失或NF-κ B B抑制导致导管树变小，分支变少。另一方面，过度表达的埃达导致显着的NF-κ B依赖性表型，在女性和男性小鼠的特点是早熟和高度增加的导管生长和分支，与增强的细胞增殖。我们已经确定了几个推定的转录靶基因Eda/NF-κ B，包括PTHrP，Wnt 10 a，和Wnt 10 B，以及Egf家族配体双调蛋白和epigen。我们开发了一种乳腺芽培养系统，使我们能够操纵离体乳腺发育，并发现重组PTHrP，Wnt 3A和Egf家族配体刺激胚胎分支形态发生，这表明这些途径可能协同介导的影响，埃达。
Ductal growth of the mammary gland occurs in two distinct stages. The first round of branching morphogenesis occurs during embryogenesis, and the second round commences at the onset of puberty. Currently, relatively little is known about the genetic networks that control the initial phases of ductal expansion, which, unlike pubertal development, proceeds independent of hormonal input in female mice. Here we identify NF-kappa B downstream of the TNF-like ligand ectodysplasin (Eda) as a unique regulator of embryonic and prepubertal ductal morphogenesis. Loss of Eda, or inhibition of NF-kappa B, led to smaller ductal trees with fewer branches. On the other hand, overexpression of Eda caused a dramatic NF-kappa B-dependent phenotype in both female and male mice characterized by precocious and highly increased ductal growth and branching that correlated with enhanced cell proliferation. We have identified several putative transcriptional target genes of Eda/NF-kappa B, including PTHrP, Wnt10a, and Wnt10b, as well as Egf family ligands amphiregulin and epigen. We developed a mammary bud culture system that allowed us to manipulate mammary development ex vivo and found that recombinant PTHrP, Wnt3A, and Egf family ligands stimulate embryonic branching morphogenesis, suggesting that these pathways may cooperatively mediate the effects of Eda.