ΔNp63 plays an anti-apoptotic role in ventral bladder development

Wei, Cheng; Jacobs, W. Bradley; Zhang, Jennifer J. R.; Moro, Anne; Park, Jin-Hyung; Kushida, Michelle; Qiu, Wei; Mills, Alea A.; Kim, Peter C.W.

doi:10.1242/dev.02621

Cited by 88 publications

(87 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, umbrella cells of the superficial layer display a distinct phenotype characterized by lack of p63 expression and presence of certain low molecular weight CKs, such as CK20 and CK18, as well as uroplakins [eg, uroplakin II (UPII) 19,20 ]. Our group and others previously found that p63 is essential for urothelial differentiation 21 and that p63-null mice developed a nontransitional default simple cubical epithelium. 22 In addition, Signoretti et al 23 reported that the urothelium of 18.5-day p63-null embryos contain a single layer that resembles umbrella cells and expresses uroplakin III (UPIII).…”

mentioning

confidence: 58%

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Karni-Schmidt

Castillo-Martín

HuaiShen

et al. 2011

The American Journal of Pathology

124

112

View full text Add to dashboard Cite

The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ⌬Np63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ⌬Np63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ⌬Np63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ⌬Np63 acting as an oncogene in certain invasive bladder tumors.

show abstract

mentioning

confidence: 58%

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Karni-Schmidt

Castillo-Martín

HuaiShen

et al. 2011

The American Journal of Pathology

124

112

View full text Add to dashboard Cite

show abstract

“…Defects of the dorsal external genitalia include epispadias with urethral defects and various dorsal external genitalia anomalies with relatively low frequency (Jeffs, 1987). Birth defects affecting the bladder, such as bladder exstrophy with associated malformation of the urethra has been reported in 1 of about 30,000-50,000 births (Cheng et al, 2006;Jeffs, 1987). Affected children often require multiple reconstructive surgical procedures (Jeffs, 1987;Johnston, 1975), increasing the impetus for research into the developmental bases of normal and abnormal urogenital organogenesis.…”

Section: Research Articlementioning

confidence: 99%

Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling

Haraguchi

Motoyama

Sasaki³

et al. 2007

Development

137

162

View full text Add to dashboard Cite

The urogenital and reproductive organs, including the external genitalia, bladder and urethra, develop as anatomically aligned organs. Descriptive and experimental embryology suggest that the cloaca, and its derivative, the urogenital sinus, contribute to the formation of these organs. However, it is unknown how the primary tissue lineages in, and adjacent to, the cloaca give rise to the above organs, nor is bladder formation understood. While it is known that sonic hedgehog (Shh) is expressed by the cloacal epithelia, the developmental programs that regulate and coordinate the formation of the urogenital and reproductive organs have not been elucidated. Here we report that Shh mutant embryos display hypoplasia of external genitalia, internal urethra (pelvic urethra) and bladder. The importance of Shh signaling in the development of bladder and external genitalia was confirmed by analyzing a variety of mutant mouse lines with defective hedgehog signaling. By genetically labeling hedgehog-responding tissue lineages adjacent to the cloaca and urogenital sinus, we defined the contribution of these tissues to the bladder and external genitalia. We discovered that development of smooth muscle myosin-positive embryonic bladder mesenchyme requires Shh signaling, and that the bladder mesenchyme and dorsal (upper) external genitalia derive from Shh-responsive peri-cloacal mesenchyme. Thus, the mesenchymal precursors for multiple urogenital structures derive from peri-cloacal mesenchyme and the coordination of urogenital organ formation from these precursors is orchestrated by Shh signals.

show abstract

“…Both TAp63 and ΔNp63 can be alternatively spliced at the 3′ terminus to produce α, β, and γ isoforms (11). ΔNp63 isoforms are selectively expressed at high levels in basal cell compartments of stratified and glandular epithelia, including in the bladder and prostate (12)(13)(14).…”

mentioning

confidence: 99%

“…Heterozygous p63 mutations underlie various human syndromes of ectodermal dysplasia, orofacial clefting, and limb malformation (15), and p63 KO mice show defects in limb, craniofacial, and epithelial development. These mice lack all stratified epithelia and their derivatives (i.e., mammary, lachrymal, and salivary glands), die at birth from dehydration, and have markedly abnormal prostate and bladder epithelia (12,13,16,17). Specific KO mice for the TA and the ΔNp63 isoforms reveal that these anomalies result from ΔNp63 absence (18,19).…”

mentioning

confidence: 99%

“…By contrast, transplants of p63 −/− urogenital sinus (UGS) revealed that luminal cells can form and regenerate in the absence of basal cells, hinting that the two cell types might represent independent cell lineages during development (12,16,25). Similarly, p63-deficient mouse urothelium contains umbrella-like cells in the absence of p63-positive basal/intermediate cells, suggesting that the cells are not related hierarchically (13,16,17). Because epithelial cell lineages in the developing bladder and prostate glands need to be further clarified, we generated knock-in mice expressing Cre recombinase (Cre) under control of the endogenous ΔNp63 promoter and performed a rigorous genetic lineage tracing analysis of ΔNp63-expressing cells in the developing caudal endoderm that gives rise to the prostate, bladder, and colorectal epithelia.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Pignon

Grisanzio

Geng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

View full text Add to dashboard Cite

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

show abstract

ΔNp63 plays an anti-apoptotic role in ventral bladder development

Cited by 88 publications

References 52 publications

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling

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

Contact Info

Product

Resources

About