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C/EBP and couple interfollicular keratinocyte proliferation arrest to commitment and terminal differentiation
Rodolphe G. Lopez1, Susana Garcia-Silva1, Susan J. Moore1, Oksana Bereshchenko1, Ana B. Martinez-Cruz2, Olga Ermakova1, Elke Kurz1, Jesus M. Paramio2 & Claus Nerlov1,3
Abstract
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 and C/EBP 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 and in the epidermis showed increased proliferation of basal keratinocytes and impaired commitment to differentiation. This led to ectopic expression of keratin 14 (K14) and 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 Np63 downregulation and K1/K10 induction. Finally, loss of C/EBP/ 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.
1 EMBL Mouse Biology Unit, Monterotondo, 00016 Italy.
2 Molecular Oncology Unit, CIEMAT, Madrid, 28040 Spain.
3 Institute for Stem Cell Research and MRC Centre for Regenerative Medicine, University of Edinburgh, UK.
