Ectodysplasin Signaling through XEDAR Is Required for Mammary Gland Morphogenesis
Ectodysplasin Signaling through XEDAR Is Required for Mammary Gland Morphogenesis
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DOI：
10.1016/j.jid.2023.02.007
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发表时间：
2023-07-14
影响因子：
6.5
通讯作者：
Kamberov，Yana G.
中科院分区：
文献类型：
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作者：
Wark，Abigail R.;Aldea，Daniel;Kamberov，Yana G.
Ectodysplasin A2 受体 (XEDAR) 是肿瘤坏死因子受体亚家族的成员，并且是 Ectodysplasin (EDA) 途径的介质。 EDA 信号在包括毛发、小汗腺和乳腺在内的外胚层附属器官类的发育中发挥着进化上保守的作用。 Eda 编码两种主要配体亚型 EDA-A1 和 EDA-A2，其功能缺失突变会导致 X 连锁少汗性外胚层发育不良，其特征是两种或多种类型的外胚层附属物缺陷。 EDA-A1 和 EDA-A2 分别通过受体 EDAR 和 XEDAR 发出信号。虽然 EDA-A1/EDAR 信号通路对 EDA 依赖性外胚层附属物表型的贡献已得到广泛表征，但该通路的 EDA-A2/XEDAR 分支的重要性仍不清楚。在此，我们报告了破坏 EDA-A2/XEDAR 通路对乳腺分化和生长的表型后果。使用小鼠 Xedarknock-out 模型，我们表明 Xedar 在促进青春期晚期生长和乳腺上皮分支方面具有特定且暂时限制的作用，该作用可能受到遗传背景的影响。我们的研究结果表明 Xedarin 外胚层附属物发育，并表明 EDA-A2/XEDAR 信号轴有助于 EDA 依赖性乳腺表型的病因学。
The Ectodysplasin A2 receptor (XEDAR), is a member of the tumor necrosis factor receptor subfamily and is a mediator of the Ectodysplasin (EDA) pathway. EDA signaling plays evolutionarily conserved roles in the development of the ectodermal appendage organ class that includes hair, eccrine sweat glands, and mammary glands. Loss of function mutations inEda, which encodes the two major ligand isoforms, EDA-A1 and EDA-A2, result in X-linked hypohidrotic ectodermal dysplasia characterized by defects in two or more types of ectodermal appendages. EDA-A1 and EDA-A2 signal through the receptors EDAR and XEDAR, respectively. While the contributions of the EDA-A1/EDAR signaling pathway to EDA-dependent ectodermal appendage phenotypes have been extensively characterized, the significance of the EDA-A2/XEDAR branch of the pathway has remained obscure. Herein, we report the phenotypic consequences of disrupting the EDA-A2/XEDAR pathway on mammary gland differentiation and growth. Using a mouseXedarknock-out model, we show thatXedarhas a specific and temporally restricted role in promoting late pubertal growth and branching of the mammary epithelium that can be influenced by genetic background. Our findings implicateXedarin ectodermal appendage development and suggest that the EDA-A2/XEDAR signaling axis contributes to the etiology ofEDA-dependent mammary phenotypes.