title: Wnt and Notch pathways have interrelated opposing roles on prostate progenitor cell proliferation and differentiation.
abstract: Tissue stem cells are capable of both self-renewal and differentiation to maintain a constant stem cell population and give rise to the plurality of cells within a tissue. Wnt signaling has been previously identified as a key mediator for the maintenance of tissue stem cells; however, possible cross-regulation with other developmentally critical signaling pathways involved in adult tissue homeostasis, such as Notch, is not well understood. By using an in vitro prostate stem cell colony ("prostasphere") formation assay and in vivo prostate reconstitution experiments, we demonstrate that Wnt pathway induction on Sca-1(+) CD49f(+) basal/stem cells (B/SCs) promotes expansion of the basal epithelial compartment with noticeable increases in "triple positive" (cytokeratin [CK] 5(+), CK8(+), p63(+)) prostate progenitor cells, concomitant with upregulation of known Wnt target genes involved in cell-cycle induction. Moreover, Wnt induction affects expression of epithelial-to-mesenchymal transition signature genes, suggesting a possible mechanism for priming B/SC to act as potential tumor-initiating cells. Interestingly, induction of Wnt signaling in B/SCs results in downregulation of Notch1 transcripts, consistent with its postulated antiproliferative role in prostate cells. In contrast, induction of Notch signaling in prostate progenitors inhibits their proliferation and disrupts prostasphere formation. In vivo prostate reconstitution assays further demonstrate that induction of Notch in B/SCs disrupts proper acini formation in cells expressing the activated Notch1 allele, Notch-1 intracellular domain. These data emphasize the importance of Wnt/Notch cross-regulation in adult stem cell biology and suggest that Wnt signaling controls the proliferation and/or maintenance of epithelial progenitors via modulation of Notch signaling.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77025, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Shahi
authors.forename: Mamatha R
authors.initials: MR
authors.lastname: Seethammagari
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Valdez
authors.forename: Li
authors.initials: L
authors.lastname: Xin
authors.forename: David M
authors.initials: DM
authors.lastname: Spencer
mesh_terms: D053687:Adult Stem Cells; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D010750:Phosphoproteins; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D015534:Trans-Activators; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein
chemical_list: C497762:Notch1 protein, mouse; D010750:Phosphoproteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D051153:Wnt Proteins; D060508:Wnt3 Protein