Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 20, Pages 8105-8110Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1221216110
Keywords
large intestine; hindgut; genitourinary tract
Categories
Funding
- National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [1R21DK72152, 1R01DK089975]
- Harvard Stem Cell Institute
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The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (Delta N) 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 Delta Np63 promoter. Heterozygote Delta Np63(+/Cre) mice were phenotypically normal and fertile. Cre-mediated recombination in Delta Np63(+/Cre); ROSA26(EYFP) reporter mice faithfully recapitulated the pattern of Delta Np63 expression and were useful for genetic lineage tracing of Delta Np63-expressing cells of the caudal endoderm in vivo. We found that Delta Np63-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 Delta Np63 expression in caudal gut endoderm and the contribution of Delta Np63-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.
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