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

Abstract

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. Cremediated 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.large intestine | hindgut | genitourinary tract

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…Additionally, co-activation of AR with the C-terminal domain of Gli2 regulates androgen-responsive genes in prostate cancer cells (41). Given the fact that p63-expressing basal cells are essential for prostate sphere formation and prostate development (21,35), future studies of whether and how p63 ϩ , CK5 ϩ , and CK8 ϩ and total number of cells in tubules from Kras(G12D)ϩARϩvector and Kras(G12D)ϩARϩshGli1/2 regenerated tissues was counted. The percentage of each type of cells was calculated.…”

P63 in health and cancer

“…They induce different target genes (Dohn et al, 2001, Wu et al, 2003. DNp63 is fundamental for the maintenance of the stem and progenitor cells in stratified epithelial and glandular tissues (Pignon et al, 2013, Senoo et al, 2007. TAp63 has a role in female germ cell preservation (Suh et al, 2006), in protection against cancer metastasis (Melino, 2011, Su et al, 2010 and in senescence (Flores et al, 2005).…”

Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages

“…Furthermore, using a lineage-tracing approach, Choi et al 7 demonstrated that basal and luminal cells in adult mouse prostates are independent self-sustaining lineages during prostate regeneration. However, using the same approach, other groups reported that in addition to unipotent luminal cells, basal cells can act as multipotent stem cells during prostate development or regeneration [8][9][10] .…”