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First published online March 15, 2004
doi: 10.1242/10.1242/dev.01089
Review |
Departments of Pediatrics, Medicine, and Cellular and Molecular Medicine, University of California, San Diego, CA 92093-0693, USA
Author for correspondence (e-mail:
snigam{at}ucsd.edu)
SUMMARY
Branching morphogenesis in the kidney is a tightly regulated, complex process and its disruption potentially can lead to a broad spectrum of diseases, ranging from rare hereditary syndromes to common conditions such as hypertension and chronic kidney failure. This review synthesizes data on branching during kidney development derived from in vitro and in vivo rodent studies and to apply them to human diseases. It discusses how the broad organization of molecular interactions during kidney development might provide a mechanistic framework for understanding disorders related to aberrant branching.
Introduction
Formation of a tree-like structure via the ramification of epithelial tubules during embryogenesis is known as branching morphogenesis. This process is fundamental to the development of a number of organ systems that share similar tissue architecture, such as the kidney, lung, breast and salivary gland. In the mammalian kidney, branching morphogenesis leads to the formation of the urinary collecting system, and a number of key developmental pathways have now been identified through the study of model systems. These have provided important insights into the mechanisms of disease that result from alteration of the branching program. Defective branching may result in clinical phenotypes that range from complete renal agenesis to diseases, such as hypertension, that exist in the setting of grossly normal appearing kidneys.
This review focuses on the intersection between human kidney disease with in vitro model systems and in vivo mutation data with the aim of correlating established molecular events in kidney development, particularly in the context of branching morphogenesis, with final renal architecture, function and pathology. These events are reviewed in the context of the morphological steps that occur during kidney development, from ureteric bud outgrowth to the cessation of branching.
Kidney organogenesis
The mammalian kidney, or metanephros, arises at approximately day 35 of
human gestation. The kidney originates from two mesenchymally derived
components: the Wolffian duct and the metanephric mesenchyme (MM). Directed by
inductive signals emanating from the MM, the Wolffian duct forms an epithelial
out-pouching called the ureteric bud (UB), which invades the adjacent MM cell
cluster. A remarkable series of events follow; reciprocal induction between
the UB and MM leads to multiple iterations of branching and elongation of the
UB to form the collecting system (where final production of a concentrated
urine occurs), while the mesenchyme is induced to condense and epithelialize
around the branched tips. Known as the mesenchymal-to-epithelial
transformation, these pre-tubular mesenchymal aggregates then proceed through
several morphological stages, including comma- and S-shaped bodies, forming
metanephric tubules that eventually mature into the parts of the nephron
responsible for regulation of ion and organic molecule transport (proximal and
distal tubules), as well as the epithelial glomerular (filtering) components
(Fig. 1A).
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15 times during human
development, normally generating between 300,000 and 1 million nephrons per
human kidney (Nyengaard and Bendtsen,
1992
). The formation of lateral branches (i.e. branches that grow
out from a main stem) is followed by terminal bifid branching (bifurcation of
one stem into two daughter branches). As each ureteric tip connects to a
nephron, it effectively is removed effectively from further branching events.
This type of branching appears to induce the majority of nephrons formed
initially. The remaining fraction develops through the poorly understood
process of arcade formation and late-phase branching
(al-Awqati and Goldberg, 1998;
Bush et. al, 2004b). The
formation of the renal calyces and renal pelvis – the part of the
urinary collecting system that leads to the ureter – occurs through the
growth and dilation of early branching segments
(Fig. 1B). There is great
variability in the number of nephrons per kidney between animal species and
currently it is unknown whether similar modes of branching occur across
species (Moritz et al.,
2003).
Ureteric bud outgrowth
In vitro studies have shown that glial cell-derived neurotrophic factor
(GDNF), produced in the MM, is a primary inducer of ureteric budding
(Sainio et al., 1997). GDNF
interacts with a number of different molecules to play a crucial role in the
initiation of downstream branching events. In mice, knockout of GDNF, or
factors that affect GDNF expression or signaling, can result in phenotypes
ranging from renal agenesis to rudimentary UB systems and kidneys. These
factors have been comprehensively reviewed
(Steer et al., 2003;
Bush et al., 2004b) and
include Wilms tumor-suppressor gene 1 (Wt1), Lim1,
Paired-box gene 2 (Pax2), Eyes absent 1 (Eya1),
Six1, Sal-like 1 (Sall1) and the Hox11 homeobox
gene paralogous group (Davis et al.,
1995; Kreidberg et al.,
1993; Laclef et al.,
2003; Nishinakamura et al.,
2001; Shawlot and Behringer,
1995; Torres et al.,
1995; Xu et al.,
1999) (see Table 1
for details). In addition, knockout of GFR
1 and Ret, members
of the GDNF receptor signaling complex, can also lead to the failure of UB
outgrowth and result in renal agenesis
(Cacalano et al., 1998;
Schuchardt et al., 1996). In
many of these knockouts, penetrance is variable; a certain percentage of
mutants have rudimentary ureteric bud systems and kidneys
(Table 2), indicating that
there are compensatory mechanisms that allow kidney development to proceed
despite disruption of the GDNF pathway. Conversely, the depletion of factors
that limit the expression of GDNF in the MM, such as Foxc1 (Mf1), or that
antagonize inductive signals from the MM, such as BMP4, leads to supernumerary
budding and duplication of the collecting system
(Kume et al., 2000;
Miyazaki et al., 2000).
|
|
;
Paine-Saunders et al., 2000).
HSPGs are glycoproteins that are found on the cell surface and within the
extracellular matrix. They are molecules with two distinct components: a core
protein and a covalently linked glycosaminoglycan (GAG) side chain, heparan
sulfate (HS). Many growth factors bind to the HS side chains of HSPGs, and the
specificity of these interactions is often based on the location and
clustering of sulfate modifications along segments of the HS chain (e.g. the
degree of 2-O-sulfation versus 6-O-sulfation) and the core protein family
(e.g. glypican versus syndecan) (Box
1). For example, GDNF activity is dependent on its binding to HS
(Barnett et al., 2002). BMP4
activity, instead, is dependent upon its binding to the cell surface HSPG
glypican 3 (Paine-Saunders et al.,
2000). These studies indicate that HSPGs influence budding via the
specificity of their interactions with morphogenic molecules, a theme that
recurs throughout kidney branching morphogenesis.
Defects during initial ureteric bud outgrowth
Renal agenesis is a relatively frequent congenital defect in humans. An
estimate of congenital absence of the kidney is 0.48 to 0.58 per 1000 live
births (unilateral agenesis occurs in 1/200 births and bilateral agenesis in
1/5000-1/10000 births) (Pohl et al.,
2002). Current data indicate that ureteric budding requires the
presence of GDNF as a primary inducer. In humans, renal agenesis arises from
mutation of single genes known to affect GDNF expression or signaling, for
example, in diseases such as Townes-Brock syndrome (SALL1),
Renal-coloboma syndrome (PAX2) or Branchio-Oto-Renal syndrome
(EYA1) (Abdelhak et al.,
1997; Kohlhase et al.,
1998; Sanyanusin et al.,
1995) (Table 1).
These genes are known to interact with GDNF expression or signaling in the
mouse, and the clinical phenotype of these gene mutations supports the view
that regulation of GDNF expression is a key event in ureteric outgrowth in
humans. Collecting system duplication (resulting in bifid ureter and duplex
kidney) is another common renal malformation; however, the gene mutations
leading to ectopic budding in humans have not yet been identified. A better
understanding of congenital renal abnormalities in humans will, in part,
depend on the creation of detailed large-scale databases of kidney and lower
urinary tract developmental disorders.
Early ureteric bud branching
Initial UB outgrowth is followed by iterative branching of the UB, and this
depends upon reciprocal epithelial-mesenchymal interactions
(Fig. 1A). Gradients of soluble
factors from the MM are likely to be essential for appropriate spatiotemporal
regulation of the arborization pattern
(Santos and Nigam, 1993). In
vitro, both in UB cell and isolated bud culture, conditions can be optimized
to sustain iterative branching in the absence of direct cell-cell contact
between epithelia and mesenchyme (Qiao et
al., 1999a; Sakurai et al.,
1997a). Soluble factors derived from the mesenchyme have been
found to support branching and growth so robust that structures eventually
occupy much of the matrix, and a major limitation seems to be one of cell
nutrition. Whether the reciprocal epithelial-mesenchymal interactions between
the UB and the MM are analogous to the positive feedback loops that coordinate
growth and patterning in vertebrate limb
(Laufer et al., 1994;
Sun et al., 2000) needs to be
determined.
Multiple factors regulate early branching
In vitro data indicates that GDNF continues to play a prominent role during
early branching (Qiao et al.,
1999a; Vega et al.,
1996). Transcriptional modulators of GDNF expression also
influence ureteric branching. For example, Emx2, a homeobox gene
expressed in UB epithelia during early branching, maintains expression of GDNF
in the MM. Murine Emx2 knockouts exhibit normal UB budding, but the
absence of subsequent branching events leads to rapid mesenchymal apoptosis
and renal agenesis (Miyamoto et al.,
1997). Similarly, maintenance of localized Ret expression in the
ureteric bud tips via expression of RAR, RARß2, Foxd1 and Pod1
appears to be crucial for proper branching morphogenesis
(Hatini et al., 1996;
Mendelsohn et al., 1999;
Quaggin et al., 1999).
Homozygous null mutation of Rara, Rarb2, Foxd1 and Pod1
results in decreased ureteric branching within the embryonic kidney
(Table 1).
Although GDNF plays an important role in continued branching morphogenesis,
in vitro studies indicate that, while necessary, it is not sufficient to
induce robust branching in an isolated UB culture model; other soluble factors
such as pleiotrophin are also important (Sakurai, 2001). Cell growth continues
to be prominent during this stage; however, sculpting of the UB also occurs.
Some members of the fibroblast growth factor (FGF) family have been implicated
in the early patterning of the UB. FGF1, FGF2, FGF7 and FGF10 all have
different effects on branching morphogenesis of the isolated UB
(Qiao et al., 2001). Other
factors may also operate during early branching. In vitro, hepatocyte growth
factor (HGF) induces branched tubule formation in cells embedded within a 3D
extracellular matrix (Montesano et al.,
1991; Santos and Nigam,
1993), as do the epidermal growth factor (EGF) receptor ligands
EGF, TGF and heparin binding EGF (HB-EGF), as well as amphiregulin
(Barros et al., 1995;
Sakurai et al., 1997b). Thus,
a plethora of soluble mesenchymally derived factors induce the isolated UB or
mature collecting system cells to branch. A single key factor has yet to be
identified and current studies suggest that multiple factors, perhaps acting
in combination, are required during early branching in vivo
(Perantoni et al., 1995;
Sakurai et al., 1997a;
Bush et al., 2004a).
HSPGs again feature prominently during early branching morphogenesis. GDNF,
pleiotrophin, HGF and various FGFs all bind to HS side chains of HSPGs, and
HSPGs appear to differentially modulate the activity of these growth factors
(Box 1)
(Barnett et al., 2002;
Iseki et al., 2002;
Rickard et al., 2003;
Rubin et al., 2001;
Pye et al., 1998). In
addition, mice with a gene trap mutation for heparan sulfate
2-O-sulfotransferase (Hs2st), an HS biosynthetic enzyme, die
perinatally because of renal agenesis
(Bullock et al., 1998). Mice
with this mutation appear to have normal UB outgrowth, but mesenchymal
condensation and subsequent UB branching is absent.
Hs2st–/– mice display a very consistent
phenotype, indicating that 2-O-sulfated HS plays an important role during
early branching (Table 2). It
is important to note that Hs2st, may also function at later stages of
kidney development, but termination of development at the early ureteric bud
branching stage precludes analysis of the role of Hs2st during late
branching morphogenesis.
The binding of growth factors to their receptors ultimately induces
cellular proliferation, shape changes and migration, all of which are required
for branching to occur. In UB branching, the ECM may serve several purposes in
this regard: providing a substrate for cell migration
(Pohl et al., 2000b;
Santos and Nigam, 1993),
acting as a reservoir for morphogenetic molecules (which exist in gradients)
(Pohl et al., 2000a) and
transmitting environmental information to the cell via adhesion molecules such
as integrins (Kanwar et al.,
1997; Zent et al.,
2001). Many of the ECM molecules that carry out these functions
have been shown to regulate branching morphogenesis in vitro
(Pohl et al., 2000a). For
example, an appropriate balance of matrix metalloproteinases (MMPs) and their
inhibitors – the tissue inhibitors of matrix proteinases (TIMPs) –
at tips and leading edges may result in matrix degradation that promotes both
branching and elongation (Stuart et al.,
1995; Sakurai and Nigam,
1998) (Fig. 2).
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Box 1. Heparan sulfate proteoglycans: multifunctional molecules
HSPGs are modular structures composed of a glycosaminoglycan side chain – heparan sulfate (HS) – covalently linked to a specific core protein. Two major families of plasma membrane-bound HSPGs are known as glypicans (A, red), of which there are six isoforms, and syndecans (A, blue), of which there are four isoforms. Each of the core protein families has distinct functions and tissue specific expression. Minor members of the HSPG superfamily include collagen XVIII (A, white), perlecan and agrin.
Heparan sulfate chain synthesis occurs in the Golgi compartment and is
mediated by a variety of biosynthetic enzymes. HS chains are composed of
alternating uronic acid and D-glucosamine residues (B) of varying lengths.
Following chain polymerization, a series of enzymes modify the HS chain
through variable sulfation and C-5 epimerization (of D-glucuronic acid to
L-iduronic acid). Variable sulfation can occur at the HNAc- residue (red
residue in B) (mediated by the N-deacetylase/N-sulfotransferase enzymes), or
at the 6-O (green), 2-O (orange) or 3-O (blue) positions (mediated by the
respective O-sulfotransferase enzymes)
(Esko and Lindahl, 2001
HSPGs play multiple roles by interacting with growth factors: they bind
growth factors in proximity to high affinity receptors, act as co-receptors in
the growth-factor-receptor complex and protect growth factors from proteolytic
degradation (reviewed by Bernfield et al.,
1999
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Defects during early branching
Aside from complete renal agenesis, very few knockout mutations of genes
that operate during early branching result in moderate to severe branching
defects (e.g. of the order of 5-10 branching generations)
(Table 1). Instead, these
phenotypes tend to be slight or undetectable. Fgf7-null mice are
characterized by mildly affected phenotypes, having only 30% fewer nephrons
than wild type (equivalent to loss of less than one branching generation),
although the overall branching architecture is maintained
(Qiao et al., 1999b).
Wnt11-null mice have a similar defect; these kidneys are
characterized by 36% fewer nephrons than wild type with no apparent
abnormality in branching pattern (Majumdar
et al., 2003).
The lack of moderate to severe branching defects may arise from a
requirement for a crucial number of nephrons for organ survival. For example,
defects in early branching processes can result in malformed (dysplastic)
kidneys that can involute eventually
(Hiraoka et al., 2002). In
addition, mechanisms such as redundancy may allow for activation of
compensatory processes that are able to buffer the effects of genetic
mutations (Melton, 1994;
Wagner, 2000). For example,
although individual disruption of Hoxa11 or Hoxd11 produces
no apparent kidney defects (Small and
Potter, 1993; Davis and
Capecchi, 1994; Davis et al.,
1995), double mutants (Hoxa11/Hoxd11) demonstrate
variable kidney hypoplasia (Davis et al.,
1995; Patterson et al.,
2001) and removal of the last Hox11 paralogous member,
Hoxc11, results in renal agenesis
(Wellik et al., 2002).
Similarly, null mutations of a number of Fgf genes (e.g. Fgf1, Fgf2, Fgf3,
Fgf5, Fgf6, Fgf9), another set of growth factors important for in vitro
UB branching, result in kidneys that, with respect to growth and branching,
appear normal, raising the possibility that substitution of function occurs
between these proteins (Kanwar et al.,
1997; Mahmood et al.,
1995; Okada-Ban et al.,
2000; Qiao et al.,
2001). Moreover, in vitro data indicate that certain combinations
of growth factors may also result in phenotypically equivalent branching; the
addition of TGFß and FGF7 to UB culture results in a tree that appears
similar to one cultured in the presence of FGF1 alone
(Bush et al., 2004a).
Finally, gene dose may also play a role in the lack of moderate to severe
branching defects. In other words, expression of the gene product must reach a
certain threshold for normal branching to occur; below the threshold
abnormalities in renal branching may result. For example, although
Gdnf null mice lack kidneys and die, heterozygotes show an array of
renal phenotypes ranging from small kidneys bilaterally (with approximately a
30% decrease in nephron number) to unilateral agenesis with no intermediate
phenotypes (Cullen-McEwen et al.,
2001). A similar requirement for adequate gene dose may be
operative in human urinary tract development, as highlighted in distal 10q
monosomy. In this condition, individuals carrying a single copy of the genes
present on the distal 10q chromosome display urinary anomalies such as small
under-developed kidneys and defects in the posterior urethral valves. The
gene(s) responsible for the observed phenotypes have not yet been identified.
However, in some of the cases, haploinsufficiency was not associated with the
urinary abnormality, perhaps owing to variable penetrance and/or a
dose-dependent gene-phenotype relationship
(Ogata et al., 2000). In
total, these studies indicate that functional redundancy and/or dose effects
exist during early branching.
Late branching and maturation
At some point during development, branching slows down, presumably owing to
negative feedback (i.e. corrective information) that serves to dampen the
intrinsic branching signals of the UB (slowing growth and proliferation) and
promote nephron patterning. There is evidence for these types of signals in
other model systems. For example, during the development of respiratory
appendages in the Drosophila embryo, the integration of positive and
negative feedback systems allows for proper spatiotemporal expression of
signals, and hence appropriate patterning
(Freeman, 2000). A similar
mechanism may operate when differentially expressed modulatory molecules, such
as TGFß and BMPs, act as branching inhibitors and sculptors in the
developing kidney (Bush et al.,
2004a).
Factors involved in negative feedback
Data obtained from whole organ culture suggest that members of the
TGFß superfamily (BMP2, BMP4, activin and TGFß1) have direct
inhibitory effects on the overall growth and development of the embryonic
kidney and cell lines, particularly on UB-derived components
(Rogers et al., 1993;
Piscione et al., 1997;
Raatikainen-Ahokas et al.,
2000; Sakurai and Nigam,
1997; Bush et al.,
2004a). The in vivo role of these factors has more been difficult
to elucidate, as knockout of these genes results in phenotypes that range from
early embryonic lethality (Bmp2, Bmp4)
(Zhang and Bradley, 1996) to
no overt renal phenotype (TGFß1, activin)
(Jhaveri et al., 1998;
Kulkarni et al., 1993). The
generation of conditional knockouts will help to further clarify these
functions.
Negative feedback signals may arise from the MM, perhaps timed to a
specific point in MM-derived tubule formation. Fusion between a lateral
ureteric branch and metanephric tubule
(Fig. 1A, stage F) effectively
removes the ureteric branch from further divisions
(Oliver, 1968). The `stop
signal' may even be present earlier during MM-derived tubule formation,
occurring in the earliest branching generations and/or as soon as comma- or
S-shaped bodies appear (Fig.
1A) to prevent the intertwining and fusion of branches. The
observed shift in expression of the branch-inhibitory factors, BMP2 and BMP7
(Dudley and Robertson, 1997)
and the slit proteins (which function in axon repulsive guidance)
(Piper et al., 2000) from the
condensed mesenchyme to the comma- and S-shaped bodies is consistent with this
hypothesis.
Patterning during kidney development also requires structural remodeling by
the ECM scaffolding (Fig. 2).
Specific ECM proteins can either enhance or inhibit branching in cultured
cells (Santos and Nigam,
1993; Sakurai and Nigam,
1997). In addition, differential expression of MMPs and TIMPs at
stalks and/or non-branching areas may provide feedback information that
prevents further branching and growth
(Nigam, 1995;
Ota et al., 1998;
Pohl et al., 2000a).
As in previous stages, regulatory molecules during late branching and
maturation require HSPGs for receptor binding and signaling. Signaling by BMP4
and BMP2 is modulated by glypican 3
(Paine-Saunders et al., 2000;
Takada et al., 2003), while
the activity of TGFß appears to be modulated by its binding to HSPGs with
N-sulfated HS chains (Lyon et al.,
1997). HSPGs may also function to establish the formation of
growth factor gradients that modulate patterning of the nephric tree. HSPGs
regulate the cellular distribution of Noggin, a BMP antagonist, and may
therefore regulate cellular responsiveness to BMPs in vivo through the
establishment of a BMP activity gradient
(Paine-Saunders et al.,
2002).
Derivatives of HSPGs can also influence UB branching directly. For example,
endostatin, a proteolytic cleavage product of the HSPG collagen XVIII,
inhibits branching in the isolated UB and in cell culture
(Karihaloo et al., 2001).
Although collagen XVIII is initially present throughout the ureteric
epithelium, as development progresses, its expression is lost at the ureteric
tips and becomes restricted to the stalk
(Lin et al., 2001). Endostatin
may suppress further branching specifically at the stalk as a result of this
differential spatial expression, which is evident as early as embryonic day
11.5 in the mouse.
Disorders of reduced nephron number
Defects during early or late branching may predispose to disorders of
reduced nephron number. The extent of UB branching is thought to reflect
nephron number (Oliver, 1968).
A widely discussed hypothesis (Brenner et
al., 1988) regarding the pathogenesis of certain forms of
hypertension is based on the argument that inadequate nephron number (which
correlates with reduced filtration surface area) results in increased
glomerular volume and increased mean arterial pressure (MAP), compensatory
mechanisms that have evolved to maintain adequate renal blood flow and
function. Indeed, kidney cross-transplantation experiments demonstrate that
hypertension can be `transplanted' from rat to rat and that in humans,
antihypertensive drug requirements of kidney donors and recipients become
similar (Rettig et al.,
1996). Long-term follow-up of GDNF heterozygous mice demonstrates
that aged mice (analogous to late-middle age humans) maintain normal kidney
function and blood flow despite reduced nephron number, but that MAP is
significantly elevated (Cullen-McEwen et
al., 2003). Similarly, rats that are growth restricted in utero
are found to have lower nephron number and higher MAP as compared with
controls (Lisle et al., 2003).
Finally, a recent study demonstrates a strong correlation between low nephron
number and hypertension among matched individuals involved in fatal accidents
(Keller et al., 2003). All of
these examples raise the possibility that some forms of essential hypertension
may be disorders of branching morphogenesis. Similarly, the progression of
chronic kidney failure also may be inversely proportional to nephron number
(Hughson et al., 2003). Thus,
it is conceivable that defects during early and late branching processes may
lead to the development of two very common clinical syndromes: hypertension
and progressive renal failure. Importantly, reduced nephron number reflects
only one of many possible pathogenic mechanisms that may lead to these
diseases.
The number of factors involved in the determination of nephron number is
likely to be even more complex than those listed here. It is conceivable that
genetic variants (the existence of two or more alleles at significant
frequencies in a population) that interact differently with modifiers,
suppressors and enhancers can cause subtle changes in nephron number that
eventually lead to disease. This could also explain the apparently continuous
distribution of nephron number in humans, ranging from approximately 230,000
to 1,800,000 (Nyengaard and Bendtsen,
1992). Variant alleles, identified by single-nucleotide
polymorphisms (SNPs), are a source of genetic diversity and are expected to be
neutral (or nearly so) with respect to fitness
(Fay et al., 2001). During
early and late branching, SNPs present in genes governing the branching
process may not affect the viability or gross architecture of the kidney, but
might predispose to hypertension or chronic kidney disease later in life. This
idea may be supported by the recent identification of a SNP in the MMP9 gene,
which appears to increase end-stage renal disease susceptibility in humans
(Hirakawa et al., 2003).
During branching, SNPs might be phenotypically subtle or even silent,
consistent with the observation that the branching program seems relatively
resistant to single mutations. Because of this resilience, it can be
postulated that multiple adverse SNPs in branching genes would be required for
a clinically significant decrease in nephron number. Identifying the factors
that are involved in these stages of branching may lead to candidate genes for
hypertension research and may even be useful in devising therapies.
Branching termination and tubule maintenance
Branching termination remains one of the biggest unresolved problems in
epithelial organogenesis. Developmental mechanisms must be `turned off' when
the structure reaches a certain size and maturity. In the developing kidney,
branching must cease and the caliber of the tubule lumen must be regulated.
Although clear stop signals have not yet been identified, in vitro studies
have suggested several possible candidates. During later stages of branching,
increased expression levels of negative regulators (e.g. TGFß) may
overwhelm positive growth-promoting factors (FGFs) and thereby act as stop
signals (Santos and Nigam,
1993; Stuart et al.,
2003; Bush et al.,
2004a). For example, branching of the murine inner medullary
collecting duct (mIMCD) cells is inhibited by the addition of TGFß,
leading to the formation of straight, non-branched tubular structures
(Sakurai and Nigam,
1997).
Stop/maturation signals also may be correlated with the differentiation of
the MM. Recombination assays between cultured UB and freshly isolated MM
indicate that the MM regulates tubule lumen caliber and provide signals that
induce UB branch elongation (Qiao et al.,
1999a; Steer et al.,
2003). However, branching does not extend beyond the confines of
the MM, which may provide specific stop signals during nephron formation and
maturation. Such stop signals could be short-range secreted molecules or
cell-surface proteins (Pohl et al.,
2000c). In other systems, membrane-bound ephrins act as stop and
maturation signals of epithelial morphogenesis. In C. elegans,
ephrins are thought to act as a repulsive signal that prevents the migration
of epidermal cells (George et al.,
1998). Interestingly, media conditioned by embryonic murine MM
cells upregulates expression of ephrin A5 and ephrin B2 in UB cells
(Pavlova et al., 1999)
suggesting a role for these proteins in UB branching morphogenesis.
Finally, sulfated proteoglycans may also function as stop signals of
branching, similar to their roles in other developmental systems. For example,
chondroitin sulfate proteoglycans (CSPGs) inhibit axon growth in vitro –
perhaps forming a protective `jacket' that masks the target stimulatory
molecule(s) (Bradbury et al.,
2002; Morgenstern et al.,
2002). It also is possible that changes in the proteoglycan
environment lead to either enhanced binding of inhibitory factors or
diminished activity of stimulatory factors; in effect creating gradients of
activity. This appears to be the case in Drosophila wing development,
where the expression of the HSPG dally regulates both the cellular
response to Dpp (the Drosophila TGFß/BMP protein homolog) and
the distribution of Dpp morphogen in tissues
(Fujise et al., 2003).
Disorders of branching termination
As yet, a clear clinical manifestation of disordered stop signals for
branching, e.g. a kidney with 4 million nephrons, has not been reported. In
fact, clinical studies that have measured gross kidney parameters have failed
to find large variation in normal kidney size (kidneys tend to be between
11-12 cm in length in the general population
(Brenner and Rector, 2000)).
It is possible that a high level of functional redundancy exists among the
stop signals. It also is feasible that nutritional or external factors
(retroperitoneal space constraints and/or restriction by the kidney capsule)
prohibit the generation of significantly over-branched organs.
It is plausible that molecules involved in stop mechanisms also play a role
in tubule maintenance. Aberrations in these signals then may result in
generation of cysts (thin-walled cavities arising from a single epithelial
cell) with corresponding clinical manifestations ranging from asymptomatic
(simple cysts) to end-stage kidney disease (polycystic kidney disease). For
example, Simpson-Golabi-Behmel (SGB) syndrome is a human disease characterized
by cystic renal overgrowth. The genetic basis for this disease is a mutation
in the glypican 3 gene (Gpc3)
(Pilia et al., 1996), an HSPG
that is a low-affinity receptor for the inhibitory molecule endostatin (see
above) and which modulates inhibitory and stimulatory growth factors involved
in branching (Grisaru et al.,
2001). Gpc3-null mice and individuals with SGB have
similar cystic phenotypes. Evaluation of these mice early in embryogenesis
demonstrates an increased number of UB branches when compared with controls;
thus, Gpc3 may modulate a branching stop signal(s). Furthermore, in
these mice, epithelial cysts progressively form as nephrogenesis proceeds;
therefore, it is possible that GPC3 also functions as a maintenance molecule
(Cano-Gauci et al., 1999).
Culture of Gpc3-deficient kidneys demonstrates that glypican 3
modulates the effects of FGF7, BMP7 and BMP2 during renal branching
morphogenesis, thereby mediating the activity (facilitatory or repressive) of
these growth factors (Grisaru et al.,
2001). In Gpc3-deficient mice, there is altered
regulation of FGF7, BMP7 and BMP2 that then correlates with increased
epithelial cell turnover (i.e. upregulated proliferation and apoptosis),
analogous to cyst-forming mechanisms found in human disease
(Lanoix et al., 1996).
Mechanisms of cyst formation
Gradients of stimulatory and inhibitory growth factors and other secreted
morphogenetic molecules are thought to be normally responsible for maintaining
tubule architecture (Pohl et al.,
2000c). Gradient disruption and/or alteration of regulatory
information presumably leads to an imbalance in the relative concentration of
growth and survival signals received by cells
(Sakurai and Nigam, 1998),
and may play a role in cyst development. Overexpression or upregulation of
several branch-promoting factors including HGF, TGF and EGFR are
associated with cystic phenotypes in mice
(Takayama et al., 1997). A
similar outcome is seen following the disruption of factors that inhibit
branching. For example, cystic dilation of tubules occurs in heterozygous
mutants of Bmp4 (Dunn et al.,
1997) and null mutants of Tgfb2
(Sanford et al., 1997).
Similar mechanisms may contribute to human cystic disease as well; autosomal
dominant polycystic kidney disease (ADPKD), the most common form of human
polycystic kidney disease, is associated with abnormal upregulation of
TGF and EGFR (Lee et al.,
1998).
The ECM is another component involved in tubule maintenance and cyst
formation. Its influence on epithelial cell behavior is highlighted by cell
culture models in which differences in ECM composition can result in
phenotypes ranging from branching structures to cysts. For example,
immortalized UB cells grown in a matrix of 80% type I collagen/20% Matrigel
(an ECM extracted from mouse EHS sarcoma composed of laminin, collagen IV, and
HSPGs) form branched tubules; however, when grown in 100% Matrigel matrix,
these cells form cysts, even in the presence of tubulogenic growth factors
(Sakurai et al., 1997a).
Likewise, when Madin-Darby canine kidney (MDCK) cells, which have the
properties of the kidney distal tubule and collecting duct cells, are grown in
type I collagen alone, they form branched tubules in the presence of HGF, a
potent tubulogenic factor for this cell line. However, MDCK cells grown in
collagen mixed with Matrigel form cysts even with the addition of HGF
(Santos and Nigam, 1993). ECM
remodeling by MMPs and their inhibitors (TIMPs) is also important in the
formation and maintenance of tubule structure
(Pohl et al., 2000a). In the
rat model of ADPKD, upregulation of MMP RNA occurs predominantly in cyst
lining epithelia. Treatment with the MMP inhibitor called batimastat results
in a significant reduction of cyst number
(Obermuller et al., 2001).
This mechanism may also apply to Von-Hippel-Lindau (VHL) disease, an autosomal
dominant tumor syndrome associated with cystic kidney disease. In cell
culture, VHL inactivation leads to decreased TIMP and increased MMP
levels, suggesting abnormal regulation by these cells
(Koochekpour et al., 1999).
This re-emphasizes the idea that the relative balance between MMPs and TIMPs
is important in proliferation versus stopping and, in this case, cyst versus
tubule formation.
Cilia
Although an appropriate balance of stimulatory and inhibitory growth
factors and ECM constraints normally maintains a steady state of proliferation
and apoptosis, another cellular feature is emerging as a prominent regulator
of tubular architecture: cilia. Cilia are organelles present on the apical
surface of tubule-lining epithelial cells that are thought to function as
environmental sensors, evident by the presence of many chemo- or
mechano-sensing receptors (Calvet,
2003). Loss of ciliary structure and function appears to induce
overgrowth of the epithelial cells, thereby leading to cyst formation,
although the mechanism for this remains undefined
(Bhunia et al., 2002;
Lin et al., 2003;
Morgan et al., 2002;
Hou et al., 2002;
Yoder et al., 2002). In
humans, cilia gene mutations disrupt regulation of tubule epithelial cell
proliferation, thereby resulting in cyst formation. Mutation of PKD1
and PKD2, genes that code for ciliary structural proteins, underlie
most forms of ADPKD, whereas mutations in OFD1, a gene involved in
cilia generation and structure, and are associated with X-linked dominant
polycystic kidney disease (Romio et al.,
2003). These studies underscore the importance of cilia function
in the regulation of tubule lumen diameter. However, the interactions between
cilia, growth factors and ECM proteins in the regulation of branching
morphogenesis remain undefined.
Injury/regeneration
Although branching does not occur following acute tubule injury,
regeneration employs a combination of mechanisms that overlap with those that
are involved in branching morphogenesis
(Nigam and Lieberthal, 2000).
Unlike glomerular or vascular injury, damage to the nephron tubule can be
repaired through regeneration. The most common injury response is acute
tubular necrosis (ATN), a sloughing of a large population of epithelial cells
occurring in response to oxygen deprivation or chemical insult. Although the
proximal tubule is the primary site of injury, more distal injury occurs as
well. Recovery from ATN is possible if the adjacent blood supply and basement
membrane remain intact, thereby guiding reconstitution of the polarized
epithelia. Several mechanisms of cellular repair are activated in the recovery
process, including mitosis of neighboring cells, recruitment, differentiation
and proliferation of stem cells, and basement membrane remodeling.
Tubule regeneration processes are in part often mediated by molecules that
are usually highly expressed during development such as HGF, MMPs, FGFs and
EGFR ligands (among others), and their putative roles in the recovery process
are listed in Table 3. During
regeneration, however, cellular responses to these factors may be different.
It is possible that regenerating cells can adopt radically different
strategies to repair tubule breaches using the same fundamental tools that
lead to tube formation in vitro or during development. The process of tubule
regeneration is poorly understood, but studies in other developmental systems
demonstrate that considerable plasticity exists within the transcriptional
state of polarized epithelial cells (Lin
et al., 2001). It is conceivable that, in order to replenish
tubule components, surviving epithelial cells exhibit very different behavior
to that seen during organogenesis. This may occur, for example, via a less
differentiated phenotype, reminiscent of the invasive cellular processes
(so-called `invadopodia') characteristic of MDCK or mIMCD cells undergoing
tubulogenesis in three-dimensional culture
(Stuart et al., 1995). Cells
also may adopt a strategy similar to the one that occurs during
Drosophila tracheobronchial development, whereby, after
proliferation, extreme cell shape changes primarily account for tube formation
(Samakovlis et al., 1996).
The end result is a restored, intact epithelial tubule without scar
formation.
|
; Ito et al.,
2000).
Summary/future directions
We have reviewed the molecular basis of kidney epithelial branching;
molecules thought to provide key points of control have been parsed within the
framework of stages that describe branching morphogenesis from ureteric bud
outgrowth to branching termination
(Stuart et al., 2003;
Nigam, 2003;
Bush et al., 2004a). Applied
to in vitro systems developed to date, this description may enable
characterization of the independent morphogenetic mechanisms functioning
during stages of kidney development and shed insight on disease.
Whereas secreted peptides, ECM molecules, growth and transcription factors comprise the mainstay of signals operative during branching, HSPGs have been found to interact with the majority of growth factors at each stage. As seen in other developmental systems, HSPGs may be instrumental in establishing growth factor gradients, as well as acting as morphogenetic modulators via their ability to regulate `positive' and `negative' growth factor activity. Further studies are needed to in order to understand how the integration of tremendous HSPG diversity with growth factor pathways at each branching step drive and/or regulate UB morphogenesis. Such studies may provide key information into the mechanisms underlying branching defects and disease.
As we have discussed, disruption at key points throughout kidney
development may lead to disease, including renal agenesis. However,
mutagenesis and gene deletion in animal models, including many genes thought
to be important in branching based on in vitro studies, often results in
kidneys that appear normal. Thus, as judged by these reports, relatively few
phenotypes lie between these two extremes. A decentralized network of
molecular interactions that comprise the developmental program, with
regulation at many levels, may account for this distribution
(Nigam, 2003). Loss of a
centrally acting molecule that interacts with or is connected to multiple
other molecules (e.g. GDNF) can produce irreparable downstream effects on
kidney development. However, the phenotypic consequences of knocking out other
genes (e.g. Hgf) may be buffered by the inhomogeneous wiring of
complex systems. In certain cases, the plasticity of the system allows
development to proceed via a bypass route and/or through alternative molecular
mechanisms that are phenotypically equivalent (Barabási et al., 2002;
Venter et al., 2001;
Nigam, 2003). Thus, a major
task of future studies will be to unravel this complex network of molecular
interactions, in order to decipher and predict the pathological consequences
of developmental errors. Application of microarray analysis to kidney
development and model systems is likely to provide essential information about
the (non)hierarchical structure of gene networks and key points of regulation
(Stuart et al., 2001;
Stuart et al., 2003;
Schwab et al., 2003).
ACKNOWLEDGMENTS
This review is dedicated to the memory of Robert Oden Stuart II, MD (1962-2004), who made major contributions to the field of kidney development and epithelial biology.
Footnotes
* These authors contributed equally to this review 
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