The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis
The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis
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DOI：
10.1101/gad.1795909
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发表时间：
2009-06-15
影响因子：
10.5
通讯作者：
Macara, Ian G.
中科院分区：
文献类型：
--
作者：
McCaffrey, Luke Martin;Macara, Ian G.
哺乳动物极性蛋白主要在细胞培养系统中进行研究，但对其在体内的功能知之甚少。为了解决这个问题，我们使用了一个shRNA慢病毒系统来操纵小鼠乳腺干/祖细胞中的基因表达。将Par3耗尽的干/祖细胞移植到乳腺脂肪垫中严重破坏了乳腺发育，并且腺体的特征在于导管增生、管腔填充和高度紊乱的终芽结构，其不能重塑成正常的导管结构。出乎意料的是，Par3耗尽的乳腺也具有扩增的祖细胞群体。我们确定了一种新的功能，为非典型蛋白激酶C（aPKC）的结合域的Par3在限制Par3和aPKC的顶端区域在乳腺上皮细胞在体内，并发现，乳腺形态依赖于Par3的能力，直接结合aPKC。这些结果揭示了一个新的功能Par3在体内的祖细胞分化和上皮形态发生的调节，并首次证明了一个必要的要求Par3-aPKC相互作用。
Mammalian polarity proteins have been studied predominantly in cell culture systems, and little is known about their functions in vivo. To address this issue, we used a shRNA lentiviral system to manipulate gene expression in mouse mammary stem/progenitor cells. Transplantation of Par3-depleted stem/progenitor cells into the mammary fat pad severely disrupted mammary development, and glands were characterized by ductal hyperplasia, luminal filling, and highly disorganized end bud structures that were unable to remodel into normal ductal structures. Unexpectedly, Par3-depleted mammary glands also had an expanded progenitor population. We identified a novel function for the atypical protein kinase C (aPKC)-binding domain of Par3 in restricting Par3 and aPKC to the apical region in mammary epithelia in vivo, and found that mammary morphogenesis is dependent on the ability of Par3 to directly bind aPKC. These results reveal a new function for Par3 in the regulation of progenitor differentiation and epithelial morphogenesis in vivo and demonstrate for the first time an essential requirement for the Par3-aPKC interaction.