C/EBPα and β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation
C/EBPα and β couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation
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DOI：
10.1038/ncb1960
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发表时间：
2009-10-01
影响因子：
21.3
通讯作者：
Nerlov, Claus
中科院分区：
文献类型：
--
作者：
Lopez, Rodolphe G.;Garcia-Silva, Susana;Nerlov, Claus
将滤泡间基底角质形成细胞增殖阻滞与定型和分化相结合的转录调节因子尚未确定。在这里，我们报告了碱性区域亮氨酸拉链转录因子C/EBP α和C/EBP β在基底角质形成细胞中共表达，并且随着角质形成细胞离开基底层并经历终末分化而协同上调。表皮中缺乏C/EBP α和β的小鼠显示基底角质形成细胞增殖增加和分化承诺受损。这导致基底上细胞中角蛋白14（K14）和Delta Np 63的异位表达，棘层和颗粒层蛋白的表达降低，角化不全和表皮水屏障功能缺陷。敲入突变显示，C/EBP-E2 F相互作用是控制毛囊间表皮（IFE）角质形成细胞增殖所必需的，但不是诱导棘层和颗粒层标记物，而C/EBP DNA结合是Delta Np 63下调和K1/K10诱导所必需的。最后，C/EBP α/β的缺失诱导表皮中的干细胞基因表达特征。因此，C/EBP分别通过E2 F抑制和DNA结合将基底角质形成细胞细胞周期退出与分化定型偶联，并可能起到限制表皮干细胞区室的作用。
The transcriptional regulators that couple interfollicular basal keratinocyte proliferation arrest to commitment and differentiation are yet to be identified. Here we report that the basic region leucine zipper transcription factors C/EBP alpha and C/EBP beta are co-expressed in basal keratinocytes, and are coordinately upregulated as keratinocytes exit the basal layer and undergo terminal differentiation. Mice lacking both C/EBP alpha and beta in the epidermis showed increased proliferation of basal keratinocytes and impaired commitment to differentiation. This led to ectopic expression of keratin 14 (K14) and Delta Np63 in suprabasal cells, decreased expression of spinous and granular layer proteins, parakeratosis and defective epidermal water barrier function. Knock-in mutagenesis revealed that C/EBP-E2F interaction was required for control of interfollicular epidermis (IFE) keratinocyte proliferation, but not for induction of spinous and granular layer markers, whereas C/EBP DNA binding was required for Delta Np63 downregulation and K1/K10 induction. Finally, loss of C/EBP alpha/beta induced stem cell gene expression signatures in the epidermis. C/EBPs, therefore, couple basal keratinocyte cell cycle exit to commitment to differentiation through E2F repression and DNA binding, respectively, and may act to restrict the epidermal stem cell compartment.