title: Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis.
abstract: A growing body of evidence suggests that the multifunctional protein E4F1 is involved in signaling pathways that play essential roles during normal development and tumorigenesis. We generated E4F1 conditional knockout mice to address E4F1 functions in vivo in newborn and adult skin. E4F1 inactivation in the entire skin or in the basal compartment of the epidermis induces skin homeostasis defects, as evidenced by transient hyperplasia in the interfollicular epithelium and alteration of keratinocyte differentiation, followed by loss of cellularity in the epidermis and severe skin ulcerations. E4F1 depletion alters clonogenic activity of epidermal stem cells (ESCs) ex vivo and ends in exhaustion of the ESC pool in vivo, indicating that the lesions observed in the E4F1 mutant skin result, at least in part, from cell-autonomous alterations in ESC maintenance. The clonogenic potential of E4F1 KO ESCs is rescued by Bmi1 overexpression or by Ink4a/Arf or p53 depletion. Skin phenotype of E4F1 KO mice is also delayed in animals with Ink4a/Arf and E4F1 compound gene deficiencies. Our data identify a regulatory axis essential for ESC-dependent skin homeostasis implicating E4F1 and the Bmi1-Arf-p53 pathway.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier, UMR5535, Centre National de la Recherche Scientifique, 34293 Montpellier, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Lacroix
authors.forename: Julie
authors.initials: J
authors.lastname: Caramel
authors.forename: Perrine
authors.initials: P
authors.lastname: Goguet-Rubio
authors.forename: Laetitia K
authors.initials: LK
authors.lastname: Linares
authors.forename: Soline
authors.initials: S
authors.lastname: Estrach
authors.forename: Elodie
authors.initials: E
authors.lastname: Hatchi
authors.forename: Geneviève
authors.initials: G
authors.lastname: Rodier
authors.forename: Gwendaline
authors.initials: G
authors.lastname: Lledo
authors.forename: Carine
authors.initials: C
authors.lastname: de Bettignies
authors.forename: Amélie
authors.initials: A
authors.lastname: Thépot
authors.forename: Céline
authors.initials: C
authors.lastname: Deraison
authors.forename: Karim
authors.initials: K
authors.lastname: Chébli
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Claude
authors.initials: C
authors.lastname: Sardet
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Cam
mesh_terms: D000367:Age Factors; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D000078404:Epidermal Cells; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: C489421:Bmi1 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C084953:E4f1 protein, mouse; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases