Decreased IGF type 1 receptor signaling in mammary epithelium during pregnancy leads to reduced proliferation, alveolar differentiation, and expression of insulin receptor substrate (IRS)-1 and IRS-2.
Decreased IGF type 1 receptor signaling in mammary epithelium during pregnancy leads to reduced proliferation, alveolar differentiation, and expression of insulin receptor substrate (IRS)-1 and IRS-2.
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DOI：
10.1210/en.2010-1296
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发表时间：
2011-05
期刊：
影响因子：
4.8
通讯作者：
Zhaoyu Sun;S. Shushanov;D. Leroith;T. Wood
中科院分区：
文献类型：
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作者：
Zhaoyu Sun;S. Shushanov;D. Leroith;T. Wood
IGF和IGF 1型受体（IGF-1 R）是小鼠正常乳腺发育的重要介质。IGF-I和IGF-1 R已被证明在青春期的末端芽的形成和增殖以及导管生长和分支中起作用。为了研究IGF-1 R在妊娠期和哺乳期的功能，我们建立了转基因小鼠品系，表达人显性阴性激酶死亡IGF-1 R（dnhIGF-1 R）的乳清酸性蛋白启动子控制下。我们提供的证据表明，IGF-1 R途径是必要的正常上皮细胞增殖和肺泡形成在怀孕期间。此外，我们证明了乳清酸性蛋白-dnhIGF-1 R转基因导致肺泡分化延迟，包括脂滴形成、管腔扩张和β-酪蛋白表达。对IGF-1 R信号通路的分析表明，由于dnhIGF-1 R的表达，P-IGF-1 R和P-Akt减少。我们进一步证明，IGF-1 R的破坏降低乳腺上皮细胞的信号中间体胰岛素受体底物（IRS）-1和IRS-2的表达。在催乳素和孕酮的下游信号靶点中没有观察到改变，这表明IGF-1 R的激活可能直接调节肺泡发育和分化过程中IRS-1/2的表达。这些数据表明，IGF-1 R信号是必要的正常肺泡增殖和分化，在某种程度上，通过诱导信号中间体介导肺泡发育。
The IGFs and the IGF type 1 receptor (IGF-1R) are essential mediators of normal mammary gland development in mice. IGF-I and the IGF-1R have demonstrated functions in formation and proliferation of terminal end buds and in ductal outgrowth and branching during puberty. To study the functions of IGF-1R during pregnancy and lactation, we established transgenic mouse lines expressing a human dominant-negative kinase dead IGF-1R (dnhIGF-1R) under the control of the whey acidic protein promoter. We provide evidence that the IGF-1R pathway is necessary for normal epithelial proliferation and alveolar formation during pregnancy. Furthermore, we demonstrate that the whey acidic protein-dnhIGF-1R transgene causes a delay in alveolar differentiation including lipid droplet formation, lumen expansion, and β-casein protein expression. Analysis of IGF-1R signaling pathways showed a decrease in P-IGF-1R and P-Akt resulting from expression of the dnhIGF-1R. We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate (IRS)-1 and IRS-2. No alterations were observed in downstream signaling targets of prolactin and progesterone, suggesting that activation of the IGF-1R may directly regulate expression of IRS-1/2 during alveolar development and differentiation. These data show that IGF-1R signaling is necessary for normal alveolar proliferation and differentiation, in part, through induction of signaling intermediates that mediate alveolar development.