Regulation of Prostate Branching Morphogenesis by Activin A and Follistatin

Abstract

Ventral prostate development occurs by branching morphogenesis and is an androgen-dependent process modulated by growth factors. Many growth factors have been implicated in branching morphogenesis including activins (dimers of beta(A) and beta(B) subunits); activin A inhibited branching of lung and kidney in vitro. Our aim was to examine the role of activins on prostatic development in vitro and their localization in vivo. Organ culture of day 0 rat ventral prostates for 6 days with activin A (+/- testosterone) inhibited prostatic branching and growth without increasing apoptosis. The activin-binding protein follistatin increased branching in vitro in the absence (but not presence) of testosterone, suggesting endogenous activins may reduce prostatic branching morphogenesis. In vivo, inhibin alpha subunit was not expressed until puberty, therefore inhibins (dimers of alpha and beta subunits) are not involved in prostatic development. Activin beta(A) was immunolocalized to developing prostatic epithelium and mesenchymal aggregates at ductal tips. Activin beta(B) immunoreactivity was weak during development, but was upregulated in prostatic epithelium during puberty. Activin receptors were expressed throughout the prostatic epithelium. Follistatin mRNA and protein were expressed throughout the prostatic epithelium. The in vitro evidence that activin and follistatin have opposing effects on ductal branching suggests a role for activin as a negative regulator of prostatic ductal branching morphogenesis.

Inhibition of Epithelial Ductal Branching in the Prostate by Sonic Hedgehog Is Indirectly Mediated by Stromal Cells

“…Consistent with this notion, conditioned media collected from primary stromal cell cultures inhibit prostatic epithelial cell proliferation (52). Activin A (38,39) and TGF-␤1 (40) have been shown to exert inhibitory effects on epithelial cell growth and branching morphogenesis and are found to be expressed in the prostatic stromal cells. In this regard, members of the TGF-␤ superfamily have been demonstrated to mediate the effects of Shh in several developmental systems (for reviews, see Refs.…”

Activin A, a product of fetal Leydig cells, is a unique paracrine regulator of Sertoli cell proliferation and fetal testis cord expansion

“…In addition to identifying activin A as a product of the fetal Leydig cells, we have uncovered an unusual role for this signaling protein during tubulogenesis. In many tubular organs, loss of activin A function results in ectopic epithelial branching; therefore, activin A is thought to function primarily as an inhibitor of branching morphogenesis (13,15,17). This role is not dependent upon the compartmental expression pattern of activin A.…”

“…We became specifically interested in the potential involvement of activin A in fetal testis cord development because of its well-established roles in tubulogenesis within other tissues including kidneys, salivary glands, pancreas, prostate, Wolffian ducts, and dentition (13)(14)(15)(16). Although compartmental specificity varies by tissue context, activin A often regulates epithelial patterning and development (17).…”

Increased Endogenous Estrogen Synthesis Leads to the Sequential Induction of Prostatic Inflammation (Prostatitis) and Prostatic Pre-Malignancy

“…Uniform systematic random sampling was then used to quantitate the number of positive cells on toluidine blue or immunohistochemical stained sections, as previously described. [21][22][23] In brief, the sections were examined under ϫ40 magnification; they were mapped to define tissue boundaries and were sampled at predetermined intervals along the x-and y-axes using a single point grid-counting frame. Positive cells were then scored and totaled for each respective gland, the final number being expressed as the number of positive cells per unit area.…”