XB-ART-50012Endocrinology July 1, 2014; 155 (7): 2534-44.
Essential roles of epithelial bone morphogenetic protein signaling during prostatic development.
Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.
PubMed ID: 24731097
PMC ID: PMC4060178
Genes referenced: bmp7.1 bmp7.2 bmpr1a cdknx krt12.1 lamtor2 nkx3-1 prim1 smad1 tp63
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|Figure 1. Bmp signaling was enhanced with the prostatic epithelial cell differentiation. A and B, Coronal sections of caudal body of ICR mice at P1; pSmad1/5/8 was weakly detected in the immature prostatic epithelia. C–F, Coronal sections of AP at P7 (C and D) and P14 (E and F). E and F, pSmad1/5/8 signal was more prominently observed in the differentiated luminal cells (F, red arrowhead) than that of the basal cells (F, black arrow) in the AP. UR, urethra. Epi, epithelia; M, mesenchyme. Scale bars, 100 μm.|
|Figure 2. Defective prostatic epithelial differentiation was induced in the Bmpr1a-CKO mutants prostate. A, C, E, G, I, and K, Epithelial differentiation in the AP of control mice. B, D, F, H, J, and L, Epithelial differentiation in the AP of epithelial-specific Bmpr1a-CKO mutant mice. A and B, Costaining for green fluorescent protein (GFP) and pSmad1/5/8 in the AP at P14. Mosaic expression of GFP was detected only in the AP epithelia but not in the stroma of both control and Bmpr1a-CKO specimens (green). A and C, pSmad1/5/8 was localized primarily in the prostatic epithelia. B and D, Decreased pSmad1/5/8 expression was detected in the Bmpr1a-CKO specimens. E, Control AP ducts at P14. F, Bmpr1a-CKO mutant AP at P14. G and H, Histologic section of the control (G) and Bmpr1a-CKO mutant prostate (H). I–L, Costaining for K19 and K8 at P7 and P14. K, K19 was localized in basal epithelia and K8 was localized in the luminal epithelia of the control mouse prostate at P14 (K′, white arrows). K8 and K19 were aberrantly coexpressed at P14 in the Bmpr1a-CKO specimens (L). A–D and G and H, scale bars, 50 μm. I–L, scale bars, 20 μm.|
|Figure 6. Stromal hyperplasia and inflammation with enlarged epithelial nuclear structures were observed in the Bmpr1a-CKO mutants. A, Morphology of AP in wild-type, ShhCreERT2/+;Bmpr1a-flox/+ (Control), and ShhCreERT2/+; Bmpr1a-flox/− mice at 6 months of age. B, D, and G, Histology of control AP. C, E, F, H, and I, The sections of the epithelial-specific Bmpr1a-CKO mutant AP. B–I, Sections stained with hematoxylin and eosin showed inflammatory cells in the stroma (E), stromal hyperplasia (F, black arrow head), inflammatory cells (H, black arrows), and enlarged nuclear structures (I) in the AP of Bmpr1a-CKO mice. A and B, Scale bars, 200 μm. D–F, Scale bars, 20 μm.|