Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland
Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland
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DOI：
10.1016/j.ydbio.2006.03.030
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发表时间：
2006-07-01
影响因子：
2.7
通讯作者：
Hamel, Paul A.
中科院分区：
文献类型：
--
作者：
Boras-Granic, Kata;Chang, Hong;Hamel, Paul A.
间充质和相邻上皮之间的诱导性相互信号传导产生皮肤附属物，如毛囊和乳腺。Lef 1介导的经典Writ信号是胚胎发育过程中这些皮肤附件的形态发生所必需的。为了确定典型的Writ信号在早期胚胎乳腺发育过程中的作用，我们确定了Writ信号在野生型和Lef 1缺陷胚胎胚胎发育过程中的时间和空间变化，携带Tcf/Lef 1-β gal报告基因（TOPGAL）转基因。与以前使用来自不同创始人的TOPGAL小鼠的研究相反，我们观察到Writ信号最初作用于与乳腺基板的顺序出现相关的间充质细胞。随着基板发育在12.5和15.5 dpc之间进行，Writ信号传导在乳腺上皮隔室中逐渐积累。到18.5 dpc时，半乳糖苷酶活性仅限于乳头附近的间充质和上皮细胞。在Lef 1缺陷的胚胎中，尽管Tcf 1在上皮细胞中表达，但基板#1、4和5的Writ信号从间充质到乳腺上皮的转变被阻断。这些基板最终消失的15.5 dpc，而基板2和3通常不会形成在没有Lef 1。基板1，4和5的进行性损失伴随着乳腺上皮基板附近的间充质细胞凋亡增加。虽然胚胎乳腺发育的重要因素，如FGF 7，在Lef 1缺陷动物中正常表达，但Hedgehog（Hh）信号通路的一种介质异常表达。具体而言，Shh，Ihh和Gli 2在乳腺上皮细胞中的表达水平与野生型同窝出生的Lef 1缺陷动物相似。然而，Ptc-1的信号是强烈减少的乳腺基板周围的间充质细胞在Lef 1突变体相对于野生型胚胎。Ptc-1是Hh信号传导的受体和转录靶点，Ptc-1的缺失表明Hh信号传导在Lef 1缺陷的胚胎中被阻断。因此，这些数据揭示了不同的乳腺基板Lef 1依赖的Writ信号的不同要求。他们进一步定义了胚胎乳腺发育过程中细胞整合Lef 1依赖性Wnt信号的动态变化。(c)2006年爱思唯尔公司All rights reserved.
Inductive reciprocal signaling between mesenchymal and adjacent epithelia gives rise to skin appendages such as hair follicles and mammary glands. Lef1-mediated canonical Writ signaling is required for morphogenesis of these skin appendages during embryogenesis. In order to define the role of canonical Writ signaling during early embryonic mammary gland development, we determined the temporal and spatial changes in Writ signaling during embryogenesis in wild-type and Lef1-deficient embryos harboring a Tcf/Lef1-beta gal reporter (TOPGAL) transgene. In contrast to previous studies using TOPGAL mice from a distinct founder, we observe that Writ signaling acts initially on mesenchymal cells associated with the sequential appearance of mammary placodes. As placode development progresses between 12.5 and 15.5 dpc, Writ signaling progressively accumulates in the mammary epithelial compartment. By 18.5 dpc, gal activity is confined to mesenchymal and epithelial cells near the nipple region. In Lef1-deficient embryos, the transition of Writ signaling from mesenchyme to the mammary epithelia is blocked for placodes #1, 4 and 5 despite the expression of Tcf1 in epithelial cells. These placodes ultimately disappear by 15.5 dpc, while placodes 2 and 3 typically did not form in the absence of Lef1. Progressive loss of placodes 1, 4, and 5 is accompanied by increased apoptosis in mesenchymal cells adjacent to the mammary epithelial placodes. While factors important for embryonic mammary gland development, such as FGF7, are expressed normally in Lef1-deficient animals, one mediator of the Hedgehog (Hh)-signaling pathway is aberrantly expressed. Specifically, Shh, Ihh, and Gli2 are expressed in mammary epithelial cells at levels in Lef1-deficient animals similar to wild-type littermates. However, the signal for Ptc-1 is strongly reduced in mesenchymal cells surrounding the mammary placode in Lef1 mutants relative to wild-type embryos. The loss of Ptc-1, both a receptor for and transcriptional target of Hh signaling, suggests that Hh signaling is blocked in Lef1-deficient embryos. Thus, these data reveal distinct requirements of different mammary placodes for Lef1-dependent Writ signaling. They further define dynamic changes in which cells integrate Lef1-dependent Wnt signaling during progression of embryonic mammary gland development. (c) 2006 Elsevier Inc. All rights reserved.