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First published online 19 September 2007
doi: 10.1242/dev.011270

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The development of the bladder trigone, the center of the anti-reflux mechanism

¹ Columbia University, Department of Urology, 650 West 168th Street, New York, NY 10032, USA.
² Department of Urology, New York University School of Medicine New York, NY, USA.
³ Department of Pathology, University of Michigan, MSRB1, BSRB 2049, 109 Zina Pitcher Dr, Ann Arbor, MI 481093, USA.
⁴ Department of Molecular Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

View larger version (66K): [in this window] [in a new window]   Fig. 1. The trigone is the site of the anti-reflux mechanism. (A). Schematic of the trigone at the bladder base and its connections with the ureters showing the intramural ureter segment that is normally compressed to prevent back-flow of urine to the ureters and kidneys. (B) Schematic showing compression of the intramural ureter. (C) A detailed representation of the trigone, which is thought to be composed of ureteral fibers that enter the bladder via Waldeyer's sheath, fan out across the base to form the inter-ureteric ridge and extend down toward the apex to form Bell's muscle. (D) A vibratome section from an adult mouse stained for uroplakin (red) to reveal the urothelium, and for smooth muscle alpha actin (green) to reveal smooth muscle. (E) Opened bladder showing the trigone in an adult Hoxb7-Gfp mouse. The ureter orifices (yellow) are located at the base of the trigone. (F) High magnification of the ureter orifice, showing its eyelet shape at the point it opens into the urothelium (red, uroplakin). Magnification: x100 in D,E; x200 in F.

View larger version (67K): [in this window] [in a new window]   Fig. 2. Development of the trigone. (A) Brightfield/darkfield composite showing a frontal section through an E15 embryo stained for uroplakin (red) to reveal the urothelium, and smooth muscle alpha actin (green) to reveal smooth muscle. Note the absence of muscle surrounding the intramural ureter compared with the extra-mural ureter, which already has a thick smooth coat. (B) The trigone in a newborn mouse showing the intramural ureter crossing the bladder muscle and submucosa. Note the longitudinal muscle fibers surrounding the intramural ureter. (C) The trigone in an adult mouse. (D) The bladder of a newborn mouse showing the deep folds of the lining, and the muscularis mucosa and smooth muscle layers below. (E) Higher magnification of the ureteral tunnel shown in B. (F) High-magnification image of the intramural ureter showing the longitudinal muscle fibers (green). (G) Higher magnification of the region in C showing the position in the trigone where the ureter joins. Note the longitudinal fibers that intercalate with the bladder muscle (yellow arrows). (H) The urethra in a newborn mouse showing the thick muscle coat (green) and smooth urothelial surface (red). Magnification: x50 in A-C; x100 in D,E,G,H; x200 in F.

View larger version (132K): [in this window] [in a new window]   Fig. 3. Comparison of the trigone in humans and mice. (A) A section through the human trigone at the level of the intramural ureter stained for smooth muscle alpha actin (brown). Black arrows point to the intramural muscle fibers. (B) A section through a newborn mouse showing the trigone stained for smooth muscle alpha actin (green) and the urothelium stained for uroplakin (red). The yellow arrows point to the longitudinal ureteral muscle fibers that encircle the intramural ureter. (C) Section through a human trigone showing the intramural path of the ureter and its surrounding thin layer of fibers (black arrows). (D). Section through the mouse trigone at birth showing the path of the intramural ureter, stained for uroplakin (red) to reveal the urothelium and smooth muscle alpha actin (green). The yellow arrows point to the longitudinal muscle fibers associated with the intramural ureter. Magnification: x20.

View larger version (87K): [in this window] [in a new window]   Fig. 4. Ureteral fibers contribute to the trigone. (A) Sagittal section through a Rarb2-Cre;R26RlacZ embryo at E14 showing lacZ-expressing mesenchymal cells surrounding the ureter (yellow arrowheads in all panels). Note the absence of lacZ-expressing cells in the bladder, trigone and urethra. (B) Higher magnification of a region of A. (C) Whole-mount of a newborn Rarb2-Cre;R26RlacZ urogenital tract showing lacZ-expressing smooth muscle cells lining the extra-mural and intramural ureter. (D) A section through the trigone showing lacZ-expressing cells surrounding the intramural ureter. (E) Smooth muscle uroplakin staining of a section serial to D, showing that the lacZ activity in D corresponds to smooth muscle. (F). Section through a human fetus at the same level as E, showing the ureteral muscle embedded in bladder muscle in the trigone. wd; Wolffian duct. Magnification: x100 in A; x200 in B-F.

View larger version (83K): [in this window] [in a new window]   Fig. 5. The trigone is formed predominantly from bladder muscle. (A) A sagittal section through a Sm22-Cre-R26RlacZ embryo at E14. lacZ-expressing mesenchymal cells are visible in the bladder, urethra and trigone (white arrow), but not in the ureter or Wolffian duct. (B) Section through the bladder and urethra of an adult Sm22-Cre-R26RlacZ mouse showing descendents of the urogenital sinus mesenchyme that have differentiated in the bladder and urethra muscle. (C) Section through an adult Sm22-Cre-R26RlacZ mouse showing the ureter, which has few if any lacZ-expressing cells, and its path through the bladder muscle that is extensively labeled by the Sm22-Cre transgene. (D) A section through the intramural portion of the ureter in an Sm22-Cre-R26RlacZ adult. (E) A section from the same sample as in D, stained for smooth muscle alpha actin to reveal muscle of the intramural ureter, unlabeled by the Sm22-Cre transgene. (F) Section through a comparable level of a human embryo showing the path of the intramural ureter through the bladder muscle of the trigone. Magnification: x100 in A-C; x200 in D-F.

View larger version (70K): [in this window] [in a new window]   Fig. 6. The structure of the trigone is likely to depend on intercalation of ureteral and bladder muscle. (A) A sagittal section through an E17 Pax2+/+ embryo showing the point at which the ureteral longitudinal fibers join the bladder detrusor (yellow arrows). (B) A sagittal section through a Pax2-/- littermate of that shown in A, showing the structure of the trigone region in the absence of the ureter. Note the abundant bladder and urethral muscle, and the tunnel through the bladder (red arrow) present in both wild type (A) and mutant (B). det, detrusor. Magnification: x100.

View larger version (40K): [in this window] [in a new window]   Fig. 7. Models of trigone formation. (A) Old model of trigone formation, showing the trigone to be continuous with the ureters (green), formed in large part from ureteral fibers that fan out across the surface generating the inter-ureteric ridge and Bell's muscle. Note that the trigone has been considered to form independently of the bladder. (B) Current model of trigone formation, showing a small contribution from ureteral fibers (green) and the bulk of the structure derived from bladder muscle and the space around the ureter that functions as a tunnel.

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