Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development
Timp-1 is important for epithelial proliferation and branching morphogenesis during mouse mammary development
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DOI：
10.1006/dbio.1999.9313
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发表时间：
1999-07-15
影响因子：
2.7
通讯作者：
Khokha, R
中科院分区：
文献类型：
--
作者：
Fata, JE;Leco, KJ;Khokha, R
乳腺导管形态发生的动态过程取决于受调控的上皮细胞增殖和细胞外基质（ECM）的转换。上皮细胞与基质的紧密接触决定了上皮细胞的增殖、分化和存活。尽管金属蛋白酶的组织抑制剂（Timps）调节ECM的转换，但它们在乳腺形态发生中的功能尚不清楚，我们已经描述了所有Timps （Timp-1至Timp-4）在小鼠乳腺发育的不同阶段的时空表达。Timp mrna在乳腺组织中丰富，每种mrna都表现出差异表达模式，主要定位于腔上皮细胞。Timp-1 mRNA的独特之处在于其表达仅限于上皮细胞高度增殖的阶段。为了评估Timp-1是否促进或抑制上皮细胞增殖，我们从遗传和生化角度控制了乳腺Timp-1水平，通过小鼠乳腺肿瘤病毒启动子定向Timp-1反义RNA表达，下调转基因小鼠上皮源性Timp-1，导致导管扩张增强，导管数量增加（P < 0.004）。在这些转基因中，上皮管周围基底膜的完整性，如层粘连蛋白特异性免疫观察；染色，被破坏。与这些小鼠相比，在植入重组timp -1释放颗粒（rTIMP-1）附近，导管扩张明显减弱，而在迁移的终末芽周围没有增加基底膜沉积。通过测量上皮细胞增殖和凋亡来确定导管扩张改变的基础。转染rTIMP-1的乳腺组织的腔内上皮细胞增殖增加了55% (P < 0.02)，而转染rTIMP-1的乳腺组织的终末芽细胞增殖则减少了38% （P < 0.02）。上皮细胞凋亡极少，并且不受Timp-1操作的影响。我们得出结论，Timps在乳腺形态发生中具有完整的功能，Timp-1在体内调节乳腺上皮细胞的增殖，至少部分是通过维持基底膜的完整性。(C) 1999学术出版社。
The dynamic process of mammary ductal morphogenesis depends on regulated epithelial proliferation and extracellular matrix (ECM) turnover. Epithelial cell-matrix contact closely dictates epithelial proliferation, differentiation, and survival. Despite the fact that tissue inhibitors of metalloproteinases (Timps) regulate ECM turnover, their function in mammary morphogenesis is unknown, We have delineated the spatiotemporal expression of all Timps (Timp-1 to Timp-4) during discrete phases of murine mammary development Timp mRNAs were abundant in mammary tissue, each displaying differential expression patterns with predominant localization in luminal epithelial cells. Timp-1 mRNA was unique in that its expression was limited to the stage at which epithelial proliferation was high. To assess whether Timp-1 promotes or inhibits epithelial cell proliferation we manipulated mammary Timp-1 levels, genetically and biochemically, Downregulation of epithelial-derived Timp-1 in transgenic mice, by mouse mammary tumor virus promoter-directed Timp-1 antisense RNA expression, led to augmented ductal expansion and increased number of ducts (P < 0.004). In these transgenics the integrity of basement membrane surrounding epithelial ducts, as visualized by laminin-specific immune; staining, was breached. In contrast to these mice, ductal expansion was markedly attenuated in the proximity of implanted recombinant Timp-1-releasing pellets (rTIMP-1), without an increase in basement membrane deposition around migrating terminal end buds. Epithelial proliferation and apoptosis were measured to determine the basis of altered ductal expansion. Luminal epithelial proliferation was increased by 55% (P < 0.02) in Timp-1-reduced transgenic mammary tissue and, conversely, decreased by 38% (P < 0.02) in terminal end buds by implanted rTIMP-1. Epithelial apoptosis was minimal and remained unaffected by Timp-1 manipulations. We conclude that Timps have an integral function in mammary morphogenesis and that Timp-1 regulates mammary epithelial proliferation in vivo, at least in part by maintaining basement membrane integrity. (C) 1999 Academic Press.