title: p53 and TAp63 promote keratinocyte proliferation and differentiation in breeding tubercles of the zebrafish.
abstract: p63 is a multi-isoform member of the p53 family of transcription factors. There is compelling genetic evidence that ΔNp63 isoforms are needed for keratinocyte proliferation and stemness in the developing vertebrate epidermis. However, the role of TAp63 isoforms is not fully understood, and TAp63 knockout mice display normal epidermal development. Here, we show that zebrafish mutants specifically lacking TAp63 isoforms, or p53, display compromised development of breeding tubercles, epidermal appendages which according to our analyses display more advanced stratification and keratinization than regular epidermis, including continuous desquamation and renewal of superficial cells by derivatives of basal keratinocytes. Defects are further enhanced in TAp63/p53 double mutants, pointing to partially redundant roles of the two related factors. Molecular analyses, treatments with chemical inhibitors and epistasis studies further reveal the existence of a linear TAp63/p53->Notch->caspase 3 pathway required both for enhanced proliferation of keratinocytes at the base of the tubercles and their subsequent differentiation in upper layers. Together, these studies identify the zebrafish breeding tubercles as specific epidermal structures sharing crucial features with the cornified mammalian epidermis. In addition, they unravel essential roles of TAp63 and p53 to promote both keratinocyte proliferation and their terminal differentiation by promoting Notch signalling and caspase 3 activity, ensuring formation and proper homeostasis of this self-renewing stratified epithelium.
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Metzger
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Richardson
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Knyphausen
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ramezani
authors.affiliation: Cell Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Franzen
authors.affiliation: Cell Biology, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
authors.forename: Elmon
authors.initials: E
authors.lastname: Schmelzer
authors.affiliation: Institute of Cardiology and Sports Medicine, German Sport University Cologne, Cologne, Germany.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Bloch
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carney
authors.affiliation: Institute of Developmental Biology, University of Cologne, Cologne, Germany ; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
mesh_terms: D000818:Animals; D001947:Breeding; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009833:Olfactory Pathways / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D020033:Protein Isoforms; D051880:Receptors, Notch; C488641:Tp63 protein, zebrafish; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish; D053148:Caspase 3