PUBLICATION

p53 and TAp63 promote keratinocyte proliferation and differentiation in breeding tubercles of the zebrafish

Authors
Fischer, B., Metzger, M., Richardson, R., Knyphausen, P., Ramezani, T., Franzen, R., Schmelzer, E., Bloch, W., Carney, T.J., and Hammerschmidt, M.
ID
ZDB-PUB-140317-29
Date
2014
Source
PLoS Genetics   10(1): e1004048 (Journal)
Registered Authors
Carney, Tom, Fischer, Boris, Hammerschmidt, Matthias, Metzger, Manuel, Ramezani, Thomas, Richardson, Rebecca
Keywords
Keratinocytes, Epidermis, Zebrafish, Notch signaling, Jaw, Animal sexual behavior, Embryos, Apoptosis
MeSH Terms
  • Animals
  • Breeding
  • Caspase 3/metabolism
  • Cell Differentiation/genetics
  • Cell Proliferation*
  • Keratinocytes/metabolism
  • Mice
  • Molecular Sequence Data
  • Olfactory Pathways/growth & development*
  • Olfactory Pathways/metabolism
  • Olfactory Pathways/pathology
  • Phosphoproteins/genetics*
  • Phosphoproteins/metabolism
  • Protein Isoforms/genetics
  • Protein Isoforms/metabolism
  • Receptors, Notch/metabolism
  • Trans-Activators/genetics*
  • Trans-Activators/metabolism
  • Tumor Suppressor Protein p53/genetics*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish/genetics*
  • Zebrafish/growth & development
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed
24415949 Full text @ PLoS Genet.
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.

Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping