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First published online 19 September 2007
doi: 10.1242/dev.011270
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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.
* Author for correspondence (e-mail: hendelsohn{at}gmail.com)
Accepted 27 July 2007
 |
SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Bladder, Reflux, Trigone, Ureter, Urinary tract formation, Mouse, Human
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The upper and lower urinary tract compartments join when the ureters
undergo transposition, moving from their primary insertion site in the
Wolffian ducts to the urogenital sinus epithelium, where they make final
connections in a triangular structure, known as the trigone, situated between
the bladder and urethra (Fig.
1). Our previous studies suggest that formation of these final
connections involves apoptosis, which enables the ureters to disconnect from
the Wolffian ducts, and fusion, in which the ureter orifice inserts into the
urogenital sinus epithelium at the level of the trigone
(Batourina et al., 2005
).
Precise connections between ureters and the trigone are crucial for function
of the valve mechanism that prevents back flow of urine from the bladder to
the ureters, a major cause of reflux and obstruction, which can damage the
kidney and cause severe health problems including end-stage renal disease.
Despite its central importance in urinary tract function, the origin and
role of the trigone in the anti-reflux mechanism remains controversial.
Analysis of human and animal specimens has led to the suggestion that the
trigone is structurally distinct from the bladder and urethra, differentiating
from the common nephric duct and ureter
(Hutch, 1972;
Tanagho, 1981;
Weiss, 1988;
Wesson, 1925). Other studies
suggest that the bladder muscle (detrusor) might also be part of the trigone
structure (Meyer, 1946).
Hence, a number of questions remain: what is the derivation of the trigone,
how is the anti-reflux mechanism established, and how do positional
abnormalities of the ureteric bud translate into reflux and obstruction? To
begin to address these questions, we used mouse models to study the structure
of the trigone and to determine which lineages contribute to its formation. We
find, unexpectedly, that the trigone derives largely from bladder muscle and
that ureteral fibers are an important contributor to trigone structure. A
number of studies also suggest that the ureteral pathway through the bladder
is formed by a sheath of ureteral muscle
(Waldeyer, 1892) (reviewed by
Hutch, 1972). We find,
paradoxically, that the ureteral pathway is present in the bladder wall and
forms independently of the ureter. These studies elucidate important
mechanisms controlling urinary tract assembly that are also important for
formation of the ureteral valve that is crucial for preventing reflux and
preserving renal function.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). UP3
antibody (clone #744) was a gift of Dr T. T. Sun (New York University, NY) was
applied overnight at 4°C. After washing, the secondary antibody (donkey
anti-rabbit IgG) was applied for 2 hours at room temperature. After washing
and reblocking, the tissue was incubated in (ASMA)FITC- or Cy3-conjugated
antibodies (Sigma) overnight at 4°C then washed and mounted.
Human tissues
With approval from the New York University Institutional Board of Research
Associates, lower urinary tracts were removed from four human fetuses ranging
in gestational age from 19 to 22 weeks. Informed consent was obtained by the
consulting obstetrician. The gestational ages were estimated from date of last
menstrual period as well as from sonographic measurements of crown rump and
foot length. Specimens were formalin-fixed, paraffin-embedded and serially
sectioned at 4 µm.
Immunohistochemistry for smooth muscle actin
Representative tissue sections were deparaffinized and rehydrated.
Endogenous peroxidase activity was blocked with 3% hydrogen peroxide for 5
minutes. Antigen retrieval was performed by incubating paraffin sections with
antigen unmasking solution (Vector Labs #H-3300) and microwave treatment (900
W) for 20 minutes, followed by blocking with 10% normal goat serum. Mouse
monoclonal antibody (M0851, Dako, Carpinteria, CA) was used to detect the
human smooth muscle actin. After overnight incubation at 4°C with
anti-smooth muscle actin, a biotinylated goat anti-mouse secondary antibody
was applied. Slides were then treated with avidin-biotinylated peroxidase
complex and developed in a solution containing 3,3'-diaminobenzidine
(DAB). All sections were counterstained with Hematoxylin, dehydrated, mounted
and observed by light microscopy
X-Gal histochemistry
To reveal lacZ expression, vibratome or cryostat sections were
fixed in cold 2% PFA in PBS for 5 minutes at 4°C, washed in PBS, and
stained in X-Gal solution for 2-5 hours at 37°C (5 mM potassium
ferricyanide, 5 mM potassium ferrocyanide, 2 mM magnesium chloride in PBS and
1.2 mg/ml X-Gal in dimethyl sulfate). After staining, samples were washed 2-3
times with PBS, post-fixed with 4% PFA and stored at 4°C in 80%
glycerol.
Animals and genotyping
For timed matings, males and females were placed in a cage together at
16.00-17.00 h, and the morning when the vaginal plug was visualized was taken
to be E0.5. Hoxb7-Gfp mice
(Srinivas et al., 1999) were a
kind gift from Dr Frank Costantini (Columbia University, New York, NY).
Genotyping was with PCR using primers: 5'-AGCGCGATCACATGGTCCTG-3'
and 5'-ACGATCCTGAGACTTCCACACT-3'. Pax2 mutant mice were
genotyped using the following three primers: Pax2F,
5'-CCCACCGTCCCTTCCTTTTCTCCTCA-3'; Pax2R,
5'-GAAAGGCCAGTGTGGCCTCTAGGGTG-3'; and PGK,
5'-AGACTGCCTTGGGAAAAGCGC-3'. Sm22-Cre mice
(Holtwick et al., 2002) were
obtained from the Jackson Laboratory and genotyped by PCR using:
5'-CAGACACCGAAGCTACTCTCCTTCC-3' and
5'-CGCATAACCAGTGAAACAGCATTGC-3'. Rosa26 lacZ mice
(Soriano, 1999) were also
obtained from the Jackson Laboratory and genotyped using:
5'-AAAGTCGCTCTGAGTTGTTAT-3',
5'-GCGAAGAGTTTGTCCTCAACC-3' and
5'-GGAGCGGGAGAAATGGATATG-3'. Rarb2-Cre mice were
genotyped as described (Kobayashi et al.,
2005).
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Development of the trigone
The trigone has been defined in a number of ways; here, we will consider
the trigone to be the muscular triangle bounded laterally by the ureter
orifices extending posteriorly to the urethra
(Fig. 1C). The unique features
of the trigone including its appearance and physiological properties have led
to the idea that the trigone originates from non-urogenital sinus tissue, in
particular from the common nephric duct that is the caudal-most segment of
Wolffian duct. However, our previous studies suggest that this is not the case
because the common nephric duct undergoes apoptosis during ureter
transposition, hence the trigone is likely to form in a different manner than
previously thought. Other studies suggest that the trigone is formed in large
part from ureteral fibers that fan out laterally forming an inter-ureteric
ridge and posteriorly forming Bell's muscle
(Fig. 1C). To begin to address
this question we first established which muscles are present in the trigone by
analyzing its formation in mouse urogenital tracts at different developmental
and post-natal stages. At E15, analysis for expression of smooth muscle alpha
actin revealed extensive smooth muscle differentiation (green) in the bladder,
urethra and in the extra-vesicular ureters (the portion of ureter outside the
bladder), but there was little if any detectable smooth muscle lining the
intramural ureter (the portion of the ureter within the bladder) in the
trigonal region (Fig. 2A).
Analysis of urogenital tracts at P0 revealed a thick smooth muscle coat
surrounding the extra-vesicular ureter and a few longitudinal fibers
surrounding the intramural ureter extending through the detrusor and submucosa
(Fig. 2B,E,F). Analysis at
adult stages revealed additional smooth muscle lining the intramural ureter.
The trigone appeared at this stage to be a hybrid between the bladder and
urethra. Its surface was smooth and free of folds like the urethra was covered
by a thick muscularis submucosa, similar to that in the bladder
(Fig. 2C,D,G,H). The ureteral
wall outside the bladder is thick, containing at least three layers of
circular and longitudinal muscle (Fig.
2E). However, as reported by other groups
(Yucel and Baskin, 2004), only
a small subset of longitudinal ureteral fibers extend into the intramural
region, where they appear to intercalate with the bladder muscle and terminate
in the submucosa, below the urothelium
(Fig. 2F,G). These findings
suggest that two major muscle types are present in the trigone: the bladder
muscle (detrusor) and the muscle associated with the intramural ureter.
Extensive analysis of whole-mount urogenital tracts, cryosections and
vibratome sections did not reveal additional muscle groups reported to be part
of the trigone, including an intra-ureteric bar which is said to extend
laterally between the two ureter orifices, and Bell's muscle which is said to
extend caudally from the ureter orifices to the trigone apex
(Tanagho et al., 1968).
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Lineage analysis reveals the origin of trigonal muscle
Ureteral muscle is thought to make a major contribution to the trigone
(Roshani et al., 1996;
Tanagho et al., 1968;
Woodburne, 1964). However,
given the complexity of the trigonal region it is not possible to determine
whether this is the case by visual inspection. To address this question, we
performed lineage studies permanently labeling smooth muscle progenitors in
the ureter using the Cre-lox recombination system. We then followed the fate
of ureteral mesenchymal cells at late stages of development to determine
whether their descendents populate the trigone. We crossed Rarb2-Cre
mice (Kobayashi et al., 2005),
which express the Cre recombinase in mesonephric mesenchyme surrounding the
nephric duct, in mesenchymal cell types within the kidney and in ureteral
mesenchyme (Kobayashi et al.,
2005), with Rosa26 lacZ reporter (R26RlacZ) mice
(Soriano, 1999). lacZ
expression is permanently activated in cells expressing both the
Rosa26 reporter and the Rarb2-Cre transgene and in their
descendents, enabling us to determine the contribution of ureteral muscle to
the trigone.
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The trigone is formed predominantly from bladder muscle
Histological studies suggest that two muscle groups reside in the trigonal
region: the detrusor muscle of the bladder and longitudinal ureteral fibers.
To assess the contribution of bladder muscle to the trigone, we permanently
labeled bladder and urethral mesenchymal muscle progenitors by crossing
R26RlacZ reporter mice with a Sm22-Cre mouse line in which
the Cre recombinase is expressed in urogenital sinus mesenchyme but not in
ureteral mesenchyme (Kuhbandner et al.,
2000) (Fig. 5).
Beginning at E12, Sm22-Cre;R26RlacZ embryos displayed extensive
lacZ activity in mesenchymal cells in the bladder, the trigone and
the urethra, but not in the ureters or Wolffian ducts
(Fig. 5A and data not shown).
By birth, expression was throughout the muscle in the bladder, trigone and
urethra, but there were few if any lacZ-labeled smooth muscle cells
in the ureter, including the intramural ureter in the trigonal region
(Fig. 5B,C). The distribution
of lacZ activity in the trigonal region of Sm22-Cre;R26RlacZ
mice was compared with that of smooth muscle alpha actin in wild-type embryos.
This revealed that there is indeed muscle present in this lateral portion of
the trigone at the ureteral junction, and that these unlabeled cells are
likely to correspond to ureteral muscle
(Fig. 5D,E). Comparison with
sections from human trigone revealed remarkable similarity in the smooth
muscle configuration: ureteral muscle was clearly present, embedded in the
bladder wall, corresponding to the unlabeled portion of the trigone in the
Sm22Cre;R26RlacZ mouse (Fig.
5D-F). Hence, ureteral fibers make a contribution to the trigone,
which is formed mainly from bladder muscle.
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) (reviewed by Hutch,
1972). Analysis of muscle differentiation in sagittal sections of
wild-type E18 embryos revealed that the ureter passes through a tunnel in the
bladder wall in parallel with blood vessels. Ureteral muscle fibers terminate
in the trigone and intersect with ureteral and bladder muscle exclusively at
its lateral edges. These findings suggest that the trigonal structure might be
formed from this pathway of the ureter through the bladder and intercalation
of the ureteral and urogenital sinus-derived fibers.
(Fig. 6A). To further address
this question, we analyzed trigone formation in the absence of the ureter in
Pax2 mutants, which display apparently normal urogenital sinus
differentiation but lack ureters and kidneys owing to agenesis of the caudal
Wolffian duct. The trigone in the Pax2 mutant shown
(Fig. 6B) contains bladder
muscle that appeared to completely encircle the bladder neck. Interestingly,
both in Pax2 mutants and in wild-type littermates, a gap was present
in the bladder wall, which probably corresponds to the ureteral tunnel. In
wild-type mice, the tunnel contained the intramural ureter and blood vessels
that pass through the muscle and submucosa into the urothelium. In
Pax2 mutants, the tunnel was also present, but contained only blood
vessels owing to the absence of the ureter. The presence of the ureteral
tunnel in the absence of ureters indicates that it is almost certainly derived
from the bladder/trigone. The observation that intercalation of ureteral and
bladder muscle occurs only at the lateral sides of the trigone is consistent
with the requirement for the ureter to maintain the raised triangular
structure normally associated with the trigone, explaining why the absence of
the ipsolateral ureter results in deformation of the trigone.
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|
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; Tanagho et al.,
1968; Wesson,
1925). The common nephric duct, which is the most caudal Wolffian
duct segment, is thought to contribute to the trigone as it differentiates and
expands during ureter transposition, repositioning the ureter orifices in the
bladder neck. However, it is unclear which portion of the trigone this tissue
would form, as the common nephric duct is an epithelial tube, an extension of
the Wolffian duct, whereas the trigonal muscle is likely to be derived from
mesenchyme, as are other muscular tissues in the embryo. Our previous findings
and the current lineage study suggest an alternate model of urinary tract
formation. We have established that the common nephric duct does not
contribute to any part of the bladder, trigone or urethra, but instead
undergoes apoptosis during ureter transposition
(Batourina et al., 2005). Here,
using Cre-lox recombination, we followed the fate of ureteral and bladder
muscle progenitors and find that the trigone is formed predominantly from
bladder muscle, with a contribution from ureteral longitudinal fibers at the
lateral edges that is much more limited than previously thought
(Fig. 7B). The intercalation of
ureteral and bladder muscle is likely to be crucial for trigone formation and
for maintaining the ureteral anti-reflux mechanism. These studies also suggest
that muscles such as Mercier's bar and Bell's muscle, which have been
considered to be formed from the ureter, are in fact derived from the bladder
(Fig. 7), as suggested by
others (Woodburne, 1964). The
observation that the trigone is formed from the same primordial tissue as the
rest of the bladder (the urogenital sinus) is consistent with studies
demonstrating that the urothelial covering of the trigone is indistinguishable
from that of the bladder, but is distinct from that of the ureter
(Liang et al., 2005).
Distinct patterning along the urinary outflow tract
Recent studies indicate that most, if not all, of the mesenchymal muscle
progenitors lining the ureter and urogenital sinus derive from the tail bud or
cloacal mesoderm (Brenner-Anantharam et
al., 2007; Haraguchi et al.,
2007). However, the morphology of these tissues is diverse.
Ureters are ensheathed by 3-4 layers of muscle that mediate myogenic
peristalsis. The bladder is surrounded by a thick layer of smooth muscle, a
muscularis mucosa and a surface composed of deep folds that enable contraction
and expansion. The trigone is smooth and has a distinctive shape probably
generated by interaction between bladder and ureteral muscle fibers at its
lateral edges. Its cellular morphology is likely to depend not on its
embryological origin, as has been suggested, but on spatially expressed
signaling molecules, including Hox genes, Bmp4, Tbx18 and
Shh, that are crucial for patterning other urinary tract tissues
(Airik et al., 2006;
Brenner-Anantharam et al.,
2007; Haraguchi et al.,
2007; Raatikainen-Ahokas et
al., 2000; Scott et al.,
2005; Yu et al.,
2002). Future studies will determine the role of these pathways in
normal trigone development and whether mutations in these genes also lead to
trigone abnormalities.
Application of this new model to human disease
The pathway taken by the ureter through the bladder muscle and submucosa is
thought to be important for function of the anti-reflux mechanism, which
normally prevents back-flow of urine to the ureters and kidney by compressing
the intramural ureter against the smooth muscle bladder wall. The ability to
effectively compress this terminal ureteral segment is thought to depend on
several factors, including sufficient length of the intramural segment, its
pathway through the bladder and insertion of the ureter orifice at a
stereotypical position in the trigone
(King et al., 1974;
Stephens et al., 1996) and
innervation that regulates opening of the ureteral orifice (reviewed by
Radmayr, 2005).
A shortening of the intramural segment, or ureter orifices joining the
trigone abnormally, can be caused by sprouting of the ureteric bud from the
Wolffian duct from a location more cranial or caudal than normal
(Mackie and Stephens, 1975;
Pope et al., 1999;
Stephens, 1983) as seen in
several mouse models (Basson et al.,
2005; Batourina et al.,
2005; Grieshammer et al.,
2004; Kume et al.,
2000; Lu et al.,
2007; Miyazaki et al.,
2000; Yu et al.,
2004), or by abnormalities in ureter transposition, at the time
when the ureter normally separates from the Wolffian duct
(Batourina et al., 2005).
Intrinsic ureteral abnormalities, such as a failure in muscle differentiation,
can also result in reflux owing to faulty urine transport or peristalsis
(Airik et al., 2006;
Chang et al., 2004;
Yu et al., 2002).
The trigone is the site at which surgery is performed to correct reflux, whereby the refluxing ureter is detached from its original insertion site and reinserted in the trigone in such a way that the length of the intramural segment is increased and has improved muscular backing. The observations from our studies that trigone formation and, by default, ureteral valve function, depend on intercalation of ureteral fibers with bladder muscle, suggest that in addition to increasing the length of the intramural ureter, reimplantation of ureters might also inadvertently help establish better connections with underlying bladder muscle and the trigone. This will further our understanding of the anti-reflux mechanism that is paramount for renal function.
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ACKNOWLEDGMENTS |
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