Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2270-5. doi: 10.1073/pnas.1019603108. Epub 2011 Jan 24.
In mammals, skin begins as a single-layered epithelium, which, through a series of signals, either stratifies and differentiates to become epidermis or invaginates downward to make hair follicles (HFs). To achieve and maintain proper tissue architecture, keratinocytes must intricately balance growth and differentiation. Here, we uncover a critical and hitherto unappreciated role for Yes-associated protein (YAP), an evolutionarily conserved transcriptional coactivator with potent oncogenic potential. We show that YAP is highly expressed and nuclear in single-layered basal epidermal progenitors. Notably, nuclear YAP progressively declines with age and correlates with proliferative potential of epidermal progenitors. Shortly after initiation of HF morphogenesis, YAP translocates to the cytoplasm of differentiating cells. Through genetic analysis, we demonstrate a role for YAP in maintaining basal epidermal progenitors and regulating HF morphogenesis. YAP overexpression causes hair placodes to evaginate into epidermis rather than invaginate into dermis. YAP also expands basal epidermal progenitors, promotes proliferation, and inhibits terminal differentiation. In vitro gain-and-loss of function studies show that primary mouse keratinocytes (MKs) accelerate proliferation, suppress differentiation, and inhibit apoptosis when YAP is activated and reverse these features when YAP is inhibited. Finally, we identify Cyr61 as a target of YAP in MKs and demonstrate a requirement for TEA domain (TEAD) transcriptional factors to comediate YAP functions in MKs.
在哺乳动物中，皮肤最初是单层上皮细胞，通过一系列信号，要么分层并分化为表皮，要么向下内陷形成毛囊 (HFs)。为了实现和维持适当的组织架构，角蛋白细胞必须精细地平衡生长和分化。在这里，我们揭示了 Yes 相关蛋白 (YAP) 的一个关键作用，这是一种进化上保守的转录共激活因子，具有潜在的致癌性。我们发现 YAP 在单层基底表皮祖细胞中高度表达并呈核定位。值得注意的是，核 YAP 随年龄的增长而逐渐下降，与表皮祖细胞的增殖潜力相关。在 HF 形态发生开始后不久，YAP 易位到分化细胞的细胞质中。通过遗传分析，我们证明了 YAP 在维持基底表皮祖细胞和调节 HF 形态发生中的作用。YAP 过表达导致毛盘向外突出到表皮中，而不是向内陷入真皮中。YAP 还扩大了基底表皮祖细胞，促进增殖，抑制终末分化。体外获得和功能丧失研究表明，当 YAP 被激活时，原代小鼠角蛋白细胞 (MKs) 会加速增殖、抑制分化和抑制细胞凋亡，而当 YAP 被抑制时，MKs 会逆转这些特征。最后，我们确定 Cyr61 是 MKs 中 YAP 的一个靶点，并证明 TEA 结构域 (TEAD) 转录因子在共介导 YAP 在 MKs 中的功能方面是必需的。
