Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling
Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling
复制标题
DOI：
10.1073/pnas.1701464114
复制
发表时间：
2017-03-21
影响因子：
11.1
通讯作者：
Werb, Zena
中科院分区：
文献类型：
--
作者：
Kessenbrock, Kai;Smith, Prestina;Werb, Zena
乳腺由脂肪组织组成，其在称为分支形态发生的过程中被包括基底和腔上皮细胞的导管上皮网络侵入。干细胞和祖细胞驱动乳腺生长，它们的增殖受多种细胞外因子的调节。这些细胞的关键调控途径之一是β-连环蛋白依赖的，典型的无翅型MMTV整合位点家族（WNT）信号传导途径;然而，乳腺干/祖细胞系统内的非典型WNT信号传导的作用仍然难以捉摸。在这里，我们专注于非经典WNT受体受体酪氨酸激酶样孤儿受体2（ROR 2）和受体样酪氨酸激酶（RYK）和它们的激活WNT 5A，标志性的非经典WNT配体之一，在乳腺上皮细胞生长和分支形态发生。我们发现WNT 5A通过受体酪氨酸激酶ROR 2在体外和体内抑制乳腺分支形态发生。出乎意料的是，WNT 5A能够增强乳腺上皮生长，这与其下一个最接近的亲属WNT 5 B相反，WNT 5 B有效地抑制乳腺干细胞/祖细胞增殖。我们发现RYK，而不是ROR 2，是WNT 5A介导的促进乳腺生长所必需的。这些发现为成人干/祖细胞调控和发育中非经典WNT信号传导的生物学提供了重要的见解。未来的研究将确定这些相互作用在乳腺癌等疾病中是如何出错的。
The mammary gland consists of an adipose tissue that, in a process called branching morphogenesis, is invaded by a ductal epithelial network comprising basal and luminal epithelial cells. Stem and progenitor cells drive mammary growth, and their proliferation is regulated by multiple extracellular cues. One of the key regulatory pathways for these cells is the beta-catenin-dependent, canonical wingless-type MMTV integration site family (WNT) signaling pathway; however, the role of noncanonical WNT signaling within the mammary stem/progenitor system remains elusive. Here, we focused on the noncanonical WNT receptors receptor tyrosine kinase-like orphan receptor 2 (ROR2) and receptor-like tyrosine kinase (RYK) and their activation by WNT5A, one of the hallmark noncanonical WNT ligands, during mammary epithelial growth and branching morphogenesis. We found that WNT5A inhibits mammary branching morphogenesis in vitro and in vivo through the receptor tyrosine kinase ROR2. Unexpectedly, WNT5A was able to enhance mammary epithelial growth, which is in contrast to its next closest relative WNT5B, which potently inhibits mammary stem/progenitor proliferation. We found that RYK, but not ROR2, is necessary for WNT5A-mediated promotion of mammary growth. These findings provide important insight into the biology of noncanonical WNT signaling in adult stem/progenitor cell regulation and development. Future research will determine how these interactions go awry in diseases such as breast cancer.