Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells
Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells
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DOI：
10.1242/dev.103333
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发表时间：
2014-03-01
期刊：
影响因子：
4.6
通讯作者：
Ewald, Andrew J.
中科院分区：
文献类型：
--
作者：
Huebner, Robert J.;Lechler, Terry;Ewald, Andrew J.
乳腺导管在发育过程中被称为末端芽（TEB）的分层上皮结构拉长。TEBs表现出减少的顶基极性和广泛的增殖。一个主要的未回答的问题是关于TEB形成过程中单纯导管上皮分层的机制。我们试图阐明这一机制，使用实时成像生长因子诱导的分层在三维培养的小鼠原代上皮类器官。我们假设分层可能是由于垂直分裂的顶部定位的管腔上皮细胞或底部定位的肌上皮细胞。在3D培养和体内，分层完全从垂直顶端细胞分裂开始。在垂直顶端分裂过程中，只有母细胞保持紧密连接和分离的顶端膜。垂直的子细胞启动了一个非极化的细胞群，位于管腔和肌上皮细胞之间，类似于TEB中的非极化体细胞。由于分层和顶端基底极性的丧失是癌症的早期标志，我们接下来确定了致癌分层的细胞机制。激活的ERBB2的表达诱导肿瘤分层通过类似的顶部定位的管腔上皮细胞的垂直分裂。然而，ERBB2诱导的分层伴随着组织过度生长和紧密连接和顶端极性的急性丧失。磷酸模拟MEK（MEK1DD），一个主要的ERBB2效应，表达也诱导分层通过垂直顶端细胞分裂。然而，表达MEK1DD的类器官表现出正常的生长水平，并保留了顶基极性。我们的结论是，正常和肿瘤分层是通过受体酪氨酸激酶信号依赖的垂直细胞分裂内管腔上皮细胞层。
Mammary ducts are elongated during development by stratified epithelial structures, known as terminal end buds (TEBs). TEBs exhibit reduced apicobasal polarity and extensive proliferation. A major unanswered question concerns the mechanism by which the simple ductal epithelium stratifies during TEB formation. We sought to elucidate this mechanism using real-time imaging of growth factor-induced stratification in 3D cultures of mouse primary epithelial organoids. We hypothesized that stratification could result from vertical divisions in either the apically positioned luminal epithelial cells or the basally positioned myoepithelial cells. Stratification initiated exclusively from vertical apical cell divisions, both in 3D culture and in vivo. During vertical apical divisions, only the mother cell retained tight junctions and segregated apical membranes. Vertical daughter cells initiated an unpolarized cell population located between the luminal and myoepithelial cells, similar to the unpolarized body cells in the TEB. As stratification and loss of apicobasal polarity are early hallmarks of cancer, we next determined the cellular mechanism of oncogenic stratification. Expression of activated ERBB2 induced neoplastic stratification through analogous vertical divisions of apically positioned luminal epithelial cells. However, ERBB2-induced stratification was accompanied by tissue overgrowth and acute loss of both tight junctions and apical polarity. Expression of phosphomimetic MEK (MEK1DD), a major ERBB2 effector, also induced stratification through vertical apical cell divisions. However, MEK1DD-expressing organoids exhibited normal levels of growth and retained apicobasal polarity. We conclude that both normal and neoplastic stratification are accomplished through receptor tyrosine kinase signaling dependent vertical cell divisions within the luminal epithelial cell layer.