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Cited by 40Developmental Biology and Gene RegulationSkin and Cellular Biology ResearchHair Growth and Disorders

p53 and TAp63 Promote Keratinocyte Proliferation and Differentiation in Breeding Tubercles of the Zebrafish

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Fischer, Boris, Metzger, Manuel, Richardson, Rebecca, Knyphausen, Philipp, Ramezani, Thomas, Franzen, Rainer, Schmelzer, Elmon, Bloch, Wilhelm +2 more·2014·PLoS Genetics
DOI 10.1371/journal.pgen.1004048PMC PMC3886889
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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.

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Authors
Fischer, B., Metzger, M., Richardson, R., Knyphausen, P., Ramezani, T., Franzen, R., Schmelzer, E., Bloch, W., Carney, T. J., & Hammerschmidt, M.
Affiliations
  • University of Cologne (DE)
  • Max Planck Institute for Plant Breeding Research (DE)
  • German Sport University Cologne (DE)
  • Institute of Molecular and Cell Biology (SG)
Corresponding author
Hammerschmidt, Matthias
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2014-01-09
Volume
10
Issue
1
Pages
e1004048
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1004048
PMC
PMC3886889
OpenAlex
W2150449510
Cited by
40
References
3
Citations by year
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FWCI
2.19
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
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  • PubMed Central (publishedVersion, cc-by)
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  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
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  • Figshare (submittedVersion, cc-by)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • Explore Bristol Research (submittedVersion)
Funders
  • European Commission (242048, LSHG-CT-2003-503496)
  • Deutsche Forschungsgemeinschaft (SFB829, SFB 829 and its Z2 project)
  • National Institutes of Health
  • National Institute of General Medical Sciences (NIH-RO1GM63904, RO1GM63904, R01GM063904)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
Keywords
p53, TAp63, ΔNp63, keratinocyte proliferation, keratinocyte differentiation, breeding tubercles, zebrafish, Notch signaling, caspase-3, epidermal development, stratified epithelium, keratinization, desquamation, epidermal appendages
MeSH terms
Animals, Breeding, Cell Differentiation, Molecular Sequence Data, Olfactory Pathways, Phosphoproteins, Zebrafish, Trans-Activators, Keratinocytes, Tumor Suppressor Protein p53, Protein Isoforms, Zebrafish Proteins, Cell Proliferation, Mice, Receptors, Notch, Caspase 3

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