Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism

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 Nkx3.1Cre and ProbasinCre alleles drive expression of Cre recombinase to the prostate epithelium and periepithelial stroma. We investigated the effects of gain of Notch function using the RosaNI1C conditional allele, which carries a constitutively active intracellular domain of Notch1 receptor. We carried out the analysis of loss of Notch function in Nkx3.1Cre/+;RBP-Jflox/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.

Research highlights
► Gain and loss of Notch function in prostate development.
► Nkx3.1Cre and PBCre4 drive Cre expression to prostate epithelium and smooth muscle.
► N1IC inhibits PTEN.
► N1IC promotes maintenance of progenitor cells in the epithelium and smooth muscle.
► Notch/RBP-J is required for differentiation of prostate epithelium and smooth muscle.