Mesenchymal Factor Bone Morphogenetic Protein 4 Restricts Ductal Budding and Branching Morphogenesis in the Developing Prostate

Abstract

The budding of the urogenital sinus epithelium into the surrounding mesenchyme signals the onset of prostate morphogenesis. The epithelial and mesenchymal factors that regulate ductal budding and the ensuing process of ductal growth and branching are not fully known. We provide evidence that bone morphogenetic protein 4 (BMP4) is a mesenchymal factor that regulates ductal morphogenesis. The Bmp4 gene was most highly expressed in the male urogenital sinus from embryonic day 14 through birth, a period marked by formation of main prostatic ducts and initiation of ductal branching. From an initial wide distribution throughout the prostatic anlage of the urogenital sinus, Bmp4 expression became progressively restricted to the mesenchyme immediately surrounding the nascent prostatic ducts and branches. Exogenous BMP4 inhibited epithelial cell proliferation and exhibited a dose-dependent inhibition of ductal budding in urogenital sinus tissues cultured in vitro. Adult Bmp4 haploinsufficient mice exhibited an increased number of duct tips in both the ventral prostate and coagulating gland. Taken together, our data indicate that BMP4 is a urogenital sinus mesenchymal factor that restricts prostate ductal budding and branching morphogenesis.

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

“…On other hand, it should be noted that BMP4, a vertebrate homolog of Drosophila Decapentaplegic, which acts as a downstream target of Shh in other tissue types (for reviews, see Refs. 9 and 51), is found to be expressed in the prostate and shown to inhibit prostatic epithelial branching (53), but its expression is not regulated by Shh based on our RT-PCT analysis (Fig. 8).…”

Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling

“…Crosstalk between HH and other signaling pathways, such as fibroblast growth factors (Fgfs), bone morphogenetic proteins (Bmps) and Wnts, and integration of these multiple inputs, is likely to be as crucial for regulating normal development of the these tissues as has been proposed in other regions of the developing embryo (Lamm et al, 2001;McMahon et al, 2003;Ovchinnikov et al, 2006;Roberts et al, 1998;Yamada et al, 2006;Zuniga et al, 1999).…”

Isolation and characterization of an immortalized mouse urogenital sinus mesenchyme cell line

“…These studies have demonstrated that the UGS mesenchyme is the target of several key signals, including testosterone, estrogen and sonic hedgehog (17)(18)(19). UGS mesenchyme is also the origin of several key morphogens including BMP-4, FGF-10, TGFβ (20)(21)(22)(23) and Shh target genes such as IGFBP-6 (Lipinski et al, submitted), which may regulate both epithelial and mesenchymal proliferation and differentiation. The complexity of these interactions is daunting.…”