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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.
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