title: Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism.
abstract: We have shown previously that during branching morphogenesis of the mouse prostate gland, Bone morphogenetic protein 7 functions to restrict Notch1-positive progenitor cells to the tips of the prostate buds. Here, we employed prostate-specific murine bi-genic systems to investigate the effects of gain and loss of Notch function during prostate development. We show that Nkx3.1(Cre) and Probasin(Cre) alleles drive expression of Cre recombinase to the prostate epithelium and periepithelial stroma. We investigated the effects of gain of Notch function using the Rosa(NI1C) conditional allele, which carries a constitutively active intracellular domain of Notch1 receptor. We carried out the analysis of loss of Notch function in Nkx3.1(Cre/+);RBP-J(flox/flox) prostates, where RBP-J is a ubiquitous transcriptional mediator of Notch signaling. We found that gain of Notch function resulted in inhibition of the tumor suppressor PTEN, and increase in cell proliferation and progenitor cells in the basal epithelium and smooth muscle compartments. In turn, loss of Notch/RBP-J function resulted in decreased cell proliferation and loss of epithelial and smooth muscle progenitors. Gain of Notch function resulted in an early onset of benign prostate hyperplasia by three months of age. Loss of Notch function also resulted in abnormal differentiation of the prostate epithelium and stroma. In particular, loss of Notch signaling and increase in PTEN promoted a switch from myoblast to fibroblast lineage, and a loss of smooth muscle. In summary, we show that Notch signaling is necessary for terminal differentiation of the prostate epithelium and smooth muscle, and that during normal prostate development Notch/PTEN pathway functions to maintain patterned progenitors in the epithelial and smooth muscle compartments. In addition, we found that both positive and negative modulation of Notch signaling results in abnormal organization of the prostate tissue, and can contribute to prostate disease in the adult organ.
authors.affiliation: Department of Urology, New York University School of Medicine, 423 East 23rd Street, New York, NY 10010, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wu
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Deng
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: Marie
authors.initials: M
authors.lastname: Monaco
authors.forename: Helen P
authors.initials: HP
authors.lastname: Makarenkova
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Herbert
authors.initials: H
authors.lastname: Lepor
authors.forename: Irina
authors.initials: I
authors.lastname: Grishina
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000196:embryology*; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C102837:Nkx3-1 protein, mouse; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse