Fig. 7. Foxa1 regulates early ductal pattern formation and promotes epithelial cell maturation. The embryonic urogenital sinus is composed of undifferentiated epithelial and stromal cells. During early prostate morphogenesis, systemic androgens and elevated epithelial cell Foxa1 and Nkx3.1 proteins modulate cell growth and differentiation. The Foxa1-null prevents cytodifferentiation and results in a population of intermediate epithelial and basal-like cells that individually express markers representative of both cell types (i.e. Ck5, Ck8 and Ck14). The mesenchymal cells differentiate into an atypically thick layer of smooth muscle. Prostatic embryonic signaling pathways remain active as reflected by the elevation of Shh, Bmp, Fgf and Notch. Foxa2, which is normally expressed only in prostatic buds in the embryo, remains elevated while Nkx3.1 is downregulated. The Foxa1-null prostate produces limited secretory proteins. An Nkx3.1-null prostate shows an epithelial cell hyperplasia by four weeks of age with limited differentiation as reflected by dramatically reduced levels of secretory proteins. By 40 weeks of age, the Nkx3.1-null prostate contains both epithelial cells hyperplasia and prostatic intraepithelial neoplasia – a precursor lesion for prostate cancer. A prostate that has AR-null epithelium but retains AR in the stromal cells results in normal development of the ductal structural, including both epithelial and basal cells. However, full differentiation does not occur as secretory proteins are not expressed. The normal adult prostate exhibits functional cytodifferentiation with fully differentiated basal and luminal cells exhibiting a full profile of secretory activity.