Department of Medicine and Endocrinology, University of California, San Francisco and Veterans Affairs Medical Center San Francisco, San Francisco, California 94121, USA.
J Invest Dermatol. 2012 Apr;132(4):1075-83. doi: 10.1038/jid.2011.430. Epub 2011 Dec 22.
The transcriptional coactivator complex Mediator (MED) facilitates transcription of nuclear hormone receptors and other transcription factors. We have previously isolated the MED complex from primary keratinocytes (KCs) as the vitamin D receptor-interacting protein complex. We identified a role for MED in KC proliferation and differentiation in cultured KCs. Here, we investigated the in vivo role of MED by generating a conditional null mice model in which a critical subunit of the MED complex, MED1, is deleted from their KCs. The MED1 ablation resulted in aberrant hair differentiation and cycling, leading to hair loss. During the first hair follicle (HF) cycle, MED1 deletion resulted in a rapid regression of the HFs. Hair differentiation was reduced, and β-catenin/vitamin D receptor (VDR)-regulated gene expression was markedly decreased. In the subsequent adult hair cycle, MED1 ablation activated the initiation of HF cycling. Shh signaling was increased, but terminal differentiation was not sufficient. Deletion of MED1 also caused hyperproliferation of interfollicular epidermal KCs, and increased the expression of epidermal differentiation markers. These results indicate that MED1 has a critical role in regulating hair/epidermal proliferation and differentiation.
转录共激活复合物 Mediator（MED）有助于核激素受体和其他转录因子的转录。我们之前已经从原代角质细胞（KC）中分离出 MED 复合物作为维生素 D 受体相互作用蛋白复合物。我们在培养的 KC 中发现 MED 在 KC 增殖和分化中的作用。在这里，我们通过生成 MED 复合物的关键亚基 MED1 从其 KC 中缺失的条件性缺失小鼠模型来研究 MED 的体内作用。MED1 的缺失导致异常的毛发分化和循环，导致脱发。在第一个毛囊（HF）周期中，HF 迅速退化。毛发分化减少，β-连环蛋白/维生素 D 受体（VDR）调节的基因表达显著降低。在下一个成人毛发生长周期中，MED1 的缺失激活了 HF 循环的启动。Shh 信号增加，但终末分化不足。MED1 的缺失还导致毛囊间表皮 KC 的过度增殖，并增加表皮分化标志物的表达。这些结果表明 MED1 在调节毛发/表皮增殖和分化方面具有关键作用。
