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The role of smooth muscle in regulating prostatic induction

¹ MRC Human Reproductive Sciences Unit, 37 Chalmers Street, Edinburgh, EH3 9ET, UK
² Division of Basic Biomedical Sciences, School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
³ Department of Anatomy, University of California, San Francisco, Parnassus Ave, San Francisco, CA 94143-0452, USA

View larger version (59K): [in a new window]   Fig. 1. Anatomy of perinatal rat urethra and associated reproductive organs. Orientation is as follows: top of figure is dorsal, bottom is ventral, left is caudal and right is cranial. (A) A P0 male rat urogenital tract: DP, dorsal prostate; DLP, dorsolateral prostate; AP, anterior prostate (also termed coagulating gland); VP, ventral prostate; UR, urethra; VD, vas deferens; BL, bladder. (C) A P0 female urogenital tract: VMP, ventral mesenchymal pad; UR, urethra; BL, bladder; Vg, vagina; Cx, cervix; Ut, uterus. (B,D) Diagrams of A,C showing the relative positions of the VP and VMP. Scale bar: 1 mm.

View larger version (58K): [in a new window]   Fig. 2. Serial section reconstruction of embryonic (E17-E20) male and female urethral UGT. The urethral epithelium (UrE) is shown in blue, SM originating from the urethra (UrSM) and bladder (BLSM) is shown in magenta, and the VMP is shown in pink. At E20, in the male, a prostatic bud emerging from the urethra is shown in yellow. Comparison of male with female shows a discontinuity between the urethral SM and the bladder SM. The VMP aligns with the SM discontinuity. In both males and females the SM is discontinuous from E17 to E19. At E20, in females the SM layer has become continuous, while in males it remains discontinuous.

View larger version (88K): [in a new window]   Fig. 3. The effect of testosterone on SM in P0 female UGTs grown in vitro. (A,B) SM distribution in P0 female UGT grown in vitro for six days in the absence of testosterone; (C,D) a similar culture to which 1x10–8 M testosterone has been added. Scale bars shown represent 100 µm. (E) UGT from a P3 female. (F) A graph of SM thickness in response to testosterone (±s.d., five experiments, 628 measurements). Testosterone treatment led to a 2.4-fold reduction in SM thickness.

View larger version (28K): [in a new window]   Fig. 4. Emergence of prostatic buds in the female UGT, and the effect of testosterone on female UGT with or without prostatic buds. (A) Five female UGTs with the VMP at the cranial end (right side). The leftmost sample shows no prostatic buds, while the next three samples show increasing bud size and proximity to the VMP, and the rightmost sample shows a bifurcated prostatic bud within the VMP. Buds are marked by an arrowhead. (B) Left side shows the effect of testosterone (T) on female UGTs without prostatic buds; right side shows female UGTs with prostatic buds grown in the presence or absence of testosterone.

View larger version (40K): [in a new window]   Fig. 5. Recombination of epithelium with female UGT/VMP. (A) A schematic diagram of the recombination, where isolated urethral epithelium was placed on top of the VMP of a female UGT, followed by 6 days growth in vitro with or without testosterone. (B) Left side shows a recombination grown in the absence of testosterone, and the recombined epithelium is indicated by arrowheads. Right side shows a recombination grown in the presence of testosterone; arrowhead shows recombined epithelium on the surface of the VMP; numerous epithelial buds can be seen extending into the VMP. Scale bar: 1 mm.

View larger version (114K): [in a new window]   Fig. 6. Immunohistochemistry for SM actin in female VMP/epithelium recombinants. (A,B) SM actin distribution in recombinants grown in the absence of testosterone. (C,D) Recombinants grown in the presence of testosterone. Arrowheads mark the recombined epithelium; arrows mark SM induced by the recombined epithelium. Scale bars: 100 µm.

View larger version (152K): [in a new window]   Fig. 7. Co-localisation studies of AR and SM. Propidium Iodide (PI) staining of nuclei is shown in red, AR is shown in green, SM is shown in blue and the merged images are shown on the right-hand side. PI/AR co-expression results in a yellow colour. (A-D) P0 male UGT, showing urethral SM (UrSM), epithelial buds of the ventral prostate (VPE) and prostatic mesenchyme (VPM). (D) UrSM contains little or no AR, whereas that SM associated with the VPE is AR positive, as is VPM. (E-H) P0 female UGT, where UrSM and VMP are visible. AR levels in the P0 female UrSM appear lower than those observed in the VMP. (I-L) A female UGT grown in vitro in the absence of testosterone; the SM layer shows lower levels of AR than the VMP. (M-P) A P0 female UGT grown in the presence of testosterone, where levels of AR in the SM layer are similar to those in the VMP. Comparison of L and P suggests that AR expression has been upregulated in the UrSM.

View larger version (19K): [in a new window]   Fig. 8. A model describing ventral prostate induction. On the left-hand side is a UGT during the initial stages of prostatic induction. The SM layer is discontinuous and signalling between the VMP and urethra occurs. At E18.5, prostatic buds become visible, in males. On the upper right side of the figure is a female at E21.5, showing the SM layer has formed and that interaction between the VMP and urethra is prevented. Residual buds may be present, but these do not enter the VMP and eventually regress. On the lower right-hand side is a male at E21.5 showing a discontinuous SM layer, prostatic buds have emerged from the urethra and entered the VMP, where subsequent growth and branching morphogenesis takes place.