title: Insulin/IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition.
abstract: The multilayered epidermis is established through a stratification program, which is accompanied by a shift from symmetric toward asymmetric divisions (ACD), a process under tight control of the transcription factor p63. However, the physiological signals regulating p63 activity in epidermal morphogenesis remain ill defined. Here, we reveal a role for insulin/IGF-1 signaling (IIS) in the regulation of p63 activity. Loss of epidermal IIS leads to a biased loss of ACD, resulting in impaired stratification. Upon loss of IIS, FoxO transcription factors are retained in the nucleus, where they bind and inhibit p63-regulated transcription. This is reversed by small interfering RNA-mediated knockdown of FoxOs. Accordingly, transgenic expression of a constitutive nuclear FoxO variant in the epidermis abrogates ACD and inhibits p63-regulated transcription and stratification. Collectively, the present study reveals a critical role for IIS-dependent control of p63 activity in coordination of ACD and stratification during epithelial morphogenesis.
authors.affiliation: Department of Dermatology, University of Cologne, 50931 Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Günschmann
authors.forename: Heike
authors.initials: H
authors.lastname: Stachelscheid
authors.forename: Mehmet Deniz
authors.initials: MD
authors.lastname: Akyüz
authors.forename: Annika
authors.initials: A
authors.lastname: Schmitz
authors.forename: Caterina
authors.initials: C
authors.lastname: Missero
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
mesh_terms: D000818:Animals; D016466:CHO Cells; D002454:Cell Differentiation; D002460:Cell Line; D003412:Cricetulus; D004817:Epidermis / Q000196:embryology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009024:Morphogenesis; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I
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