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

JC Pignon, C Grisanzio, Y Geng… - Proceedings of the …, 2013 - National Acad Sciences
JC Pignon, C Grisanzio, Y Geng, J Song, RA Shivdasani, S Signoretti
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
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 …
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;ROSA26EYFP 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.
National Acad Sciences