p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Proc Natl Acad Sci U S A. 2013 May 14;110(20):8105-10. doi: 10.1073/pnas.1221216110. Epub 2013 Apr 25.


The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (ΔN) p63 isoform, is a marker of basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder and prostate glands. Although p63-expressing cells are proposed to be the stem cells of the developing prostate epithelium and bladder urothelium, cell lineages in these endoderm-derived epithelia remain highly controversial, and rigorous lineage tracing studies are warranted. Here, we generated knock-in mice expressing Cre recombinase (Cre) under the control of the endogenous ΔNp63 promoter. Heterozygote ΔNp63(+/Cre) mice were phenotypically normal and fertile. Cre-mediated recombination in ΔNp63(+/Cre);ROSA26(EYFP) reporter mice faithfully recapitulated the pattern of ΔNp63 expression and were useful for genetic lineage tracing of ΔNp63-expressing cells of the caudal endoderm in vivo. We found that ΔNp63-positive cells of the urogenital sinus generated all epithelial lineages of the prostate and bladder, indicating that these cells represent the stem/progenitor cells of those epithelia during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon.

Keywords: genitourinary tract; hindgut; large intestine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • Cell Lineage
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knock-In Techniques
  • Genotype
  • Male
  • Metaplasia / metabolism
  • Mice
  • Mice, Transgenic
  • Neoplastic Stem Cells / cytology*
  • Neoplastic Stem Cells / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Promoter Regions, Genetic
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Protein Structure, Tertiary
  • Stem Cells / cytology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism*


  • Phosphoproteins
  • Trans-Activators
  • Trp63 protein, mouse