Notch and TGFβ Form a Reciprocal Positive Regulatory Loop that Suppresses Murine Prostate Basal Stem/Progenitor Cell Activity

• Published in: Cell stem cell 2012-11, Vol.11 (5), p.676-688
• Main Authors: Valdez, Joseph M., Zhang, Li, Su, Qingtai, Dakhova, Olga, Zhang, Yiqun, Shahi, Payam, Spencer, David M., Creighton, Chad J., Ittmann, Michael M., Xin, Li
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Differentiation; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell Proliferation; Fundamental and applied biological sciences. Psychology; Male; Mice; Microscopy, Electron, Scanning Transmission; Molecular and cellular biology; Prostate - cytology; Prostate - metabolism; Receptors, Notch - metabolism; Signal Transduction; Stem Cells - cytology; Stem Cells - metabolism; Transforming Growth Factor beta - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2012.07.003

The role of Notch signaling in the maintenance of adult murine prostate epithelial homeostasis remains unclear. We found that Notch ligands are mainly expressed within the basal cell lineage, while active Notch signaling is detected in both the prostate basal and luminal cell lineages. Disrupting the canonical Notch effector Rbp-j impairs the differentiation of prostate basal stem cells and increases their proliferation in vitro and in vivo, but does not affect luminal cell biology. Conversely, ectopic Notch activation in adult prostates results in a decrease in basal cell number and luminal cell hyperproliferation. TGFβ dominates over Notch signaling and overrides Notch ablation-induced proliferation of prostate basal cells. However, Notch confers sensitivity and positive feedback by upregulating a plethora of TGFβ signaling components including TgfβR1. These findings reveal crucial roles of the self-enforced positive reciprocal regulatory loop between TGFβ and Notch in maintaining prostate basal stem cell dormancy. ► Notch ablation results in prostate basal cell expansion during regeneration ► Notch activation suppresses the prostate basal cell lineage in vivo ► Notch induces lineage-specific biological outcomes in the prostate ► A positive feedback loop between Notch and TGFβ maintains basal stem cell dormancy A positive Notch/TGFβ feedback loop keeps basal stem cells dormant in the adult mouse prostate. Manipulating these pathways may provide a therapeutic avenue to protect basal cell loss or transformation during prostate carcinogenesis.