Wnt5a is required for proper mammary gland development and TGF-β-mediated inhibition of ductal growth
Wnt5a is required for proper mammary gland development and TGF-β-mediated inhibition of ductal growth
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DOI：
10.1242/dev.008250
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发表时间：
2007-11-01
期刊：
影响因子：
4.6
通讯作者：
Serra, Rosa
中科院分区：
文献类型：
--
作者：
Roarty, Kevin;Serra, Rosa
转化生长因子-β（TGF-β）在乳腺的生长和形成中起重要作用，并且其信号传导的改变已显示对肿瘤进展和转移的非法双相作用。我们在小鼠中证明了TGF-β（TGF β）调节无翅相关蛋白家族的非经典信号成员Wnt 5a的表达。Wnt 5a表达的缺失与乳腺癌患者的预后不良相关;然而，缺乏关于Wnt 5a在乳腺发育中的功能作用的数据。我们表明，Wnt 5a能够抑制乳腺导管的延伸和侧向分支。此外，与野生型组织相比，Wnt 5a（-/-）乳腺组织表现出加速的发育能力，其特征在于更大的末端芽、快速的导管伸长、增加的侧向分支和增加的增殖.此外，TGF-β信号传导的显性负干扰不仅影响Wnt 5a的表达，而且影响盘状结构域受体1（Ddr 1）的磷酸化，Ddr 1是一种胶原蛋白受体和参与细胞粘附/迁移的Wnt 5a的下游靶标.最后，我们表明Wnt 5a是TGF-β介导的抑制体内导管延伸和培养中分支所必需的。这项研究首次显示了正常乳腺发育中对Wnt 5a的需求及其与TGF-β的功能联系。
Transforming growth factor- beta ( TGF- beta) plays an essential role in growth and patterning of the mammary gland, and alterations in its signaling have been shown to illicit biphasic effects on tumor progression and metastasis. We demonstrate in mice that TGF- beta ( Tgf beta) regulates the expression of a non- canonical signaling member of the wingless- related protein family, Wnt5a. Loss of Wnt5a expression has been associated with poor prognosis in breast cancer patients; however, data are lacking with regard to a functional role for Wnt5a in mammary gland development. We show that Wnt5a is capable of inhibiting ductal extension and lateral branching in the mammary gland. Furthermore, Wnt5a(-/-) mammary tissue exhibits an accelerated developmental capacity compared with wild- type tissue, marked by larger terminal end buds, rapid ductal elongation, increased lateral branching and increased proliferation. Additionally, dominant- negative interference of TGF- beta signaling impacts not only the expression of Wnt5a, but also the phosphorylation of discoidin domain receptor 1 ( Ddr1), a receptor for collagen and downstream target of Wnt5a implicated in cell adhesion/ migration. Lastly, we show that Wnt5a is required for TGF- beta- mediated inhibition of ductal extension in vivo and branching in culture. This study is the first to show a requirement for Wnt5a in normal mammary development and its functional connection to TGF- beta.