1 Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030,
USA
2 Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, TX 77030, USA
3 Department of Otolaryngology, Baylor College of Medicine, Houston, TX 77030,
USA
4 Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA
* Author for correspondence (e-mail: huiz{at}bcm.tmc.edu)
Accepted 12 June 2003
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SUMMARY |
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Key words: Presenilin, Notch, Kidney, Nephrogenesis, Patterning, Proximal tubule
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Introduction |
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Organogenesis is a highly regulated developmental program involving
cell-fate decisions, pattern formation and differentiation. In mammals,
organogenesis initiates after the body axes are established. Kidney
organogenesis in mice begins at E11 and involves reciprocal inductive
interactions between the ureteric bud epithelium and metanephric mesenchyme.
The tips of the ureteric bud induce nephrogenic mesenchyme to form condensates
followed by pretubular aggregates, which then undergo mesenchyme to epithelium
transition (MET) to progress into polarized epithelia of renal vesicles and
comma- and S-shaped bodies (Saxen,
1987). Morphogenesis and patterning of the epithelial structures
then leads to the formation of distal and proximal tubules and the glomerulus;
the latter consists of podocytes, mesangial cells and endothelial cells
(Saxen, 1987
).
A number of ductal- and mesenchymal-derived molecules have been identified
and loss-of-function studies have established their crucial roles in
nephrogenesis
(http://golgi.ana.ed.ac.uk/kidhome.html).
Relevant to this study, Ret is expressed at the tips of the newly
formed branches of the ureteric bud and is crucial for the inductive
interactions through binding to its ligand GDNF, which resides in the
condensing mesenchyme (Moore et al.,
1996; Pachnis et al.,
1993
; Schuchardt et al.,
1994
). The paired box genes Pax2 and Pax8 are
expressed in various mesenchymal derivatives and ureteric bud epithelium
(Dressler et al., 1993
;
Plachov et al., 1990
;
Rothenpieler and Dressler,
1993
), and together they regulate and define the nephric lineage
(Bouchard et al., 2002
). Wnt4
has been documented as an essential signaling molecule from the metanephric
mesenchyme for the mesenchymal to epithelial cell conversion
(Kispert et al., 1998
;
Stark et al., 1994
).
WT1 is expressed in both uninduced mesenchyme and podocyte precursor
cells of S-shaped bodies and mature glomeruli. It is required in the earliest
phase of kidney formation (Armstrong et
al., 1993
; Kreidberg et al.,
1993
). The winged helix transcription factor BF2 is
specifically expressed in the interstitial stromal mesenchyme and has been
shown to modulate the transition of condensed mesenchyme into tubular
epithelium (Hatini et al.,
1996
).
The Notch pathway has been implicated in kidney development. Specifically,
Notch1 and Notch2 and their ligands Delta-like1
(Dll1) and Jag1 are expressed in the maturing nephron and
glomerulus (Beckers et al.,
1999; McCright et al.,
2001
; Weinmaster et al.,
1991
; Weinmaster et al.,
1992
). In the Xenopus pronephros, Notch signaling has
been proposed to be involved in both the early determination of duct versus
tubule fate as well as in controlling tubule patterning
(McLaughlin et al., 2000
).
Furthermore, mice with a hypomorphic expression of Notch2 exhibit a
kidney glomerulogenesis defect (McCright
et al., 2001
).
We reported earlier that restricted expression of a human PSEN1
transgene in the developing brain and vertebral/spinal column driven by the
human Thy-1 promoter could rescue the Psen1-null patterning defects
and lethal phenotype (Qian et al.,
1998). To bypass the early lethality of the PSEN null embryos, we
bred the transgene onto the Psen1- and Psen2-double knockout
background. We showed that expression of the human PSEN1 transgene
supported the survival of the PSEN-null embryos to the perinatal stage.
However, loss of presenilins resulted in profound nephrogenesis defects prior
to development of comma- and S-shaped bodies. We provide evidence that
presenilins play an important role, probably through the Notch signaling
pathway, in the patterning of renal epithelial structures.
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Materials and methods |
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In situ hybridization
In situ hybridization was carried out using digoxigenin-labeled or
[35S]UTP-labeled antisense riboprobes. Samples were fixed in 10%
neutral buffered formalin and embedded in paraffin wax. Sections were cut at 5
µm for radioactive probes and at 9 µm for nonradioactive probes. The
protocol used for radioactive in situ was essentially as published
(Qiu et al., 1994). For
non-radioactive in situ, a modified protocol of Wilkinson was employed
(Wilkinson, 1992
). In brief,
sections were dewaxed and dehydrated, then fixed in 4% paraformaldehyde (PFA)
for 30 minutes at room temperature. After washing with PBS, sections were
treated with proteinase K (20 µg/ml) for 10 minutes, refixed with PFA and
washed with PBS. Samples were acetylated for 20 minutes, washed and hybridized
(in 50% formamide, 20 mM Tris-HCl (pH 8.0), 500 µg/ml tRNA,
1xDenhardt's solution, 10% dextran sulfate, 300 mM NaCl, 10 mM
NaPO4 (pH 8.0), 5 mM EDTA) with 200 ng probe/slide overnight at
65°C in a humidified chamber. Sections were washed for 40 minutes with
0.5xSSC/20% formamide at 60°C followed by treatment with RNase for
30 minutes at 37°C, and washed again for 20 minutes with 0.5xSSC/20%
formamide at 60°C. Sections were blocked with blocking solution (100 mM
maleic acid, 150 mM NaCl, 1% Boehringer blocking agent) for 1 hour at room
temperature and incubated with alkaline phosphatase-conjugated sheep
polyclonal antidigoxigenin antibody (Roche) diluted 1:2000 in TBS buffer
overnight at 4°C. After washing twice with TBS, alkaline phosphatase
activity was detected in the presence of NBT/BCIP (Roche).
Immunohistochemical staining
PSEN-null and the littermate control kidneys were dissected at various
developmental stages as specified in the figure legends. Immunohistochemical
staining was performed in frozen (laminin 1, gift from D. Abrahamson)
or paraffin-fixed sections (all others). Sections were blocked with 5% goat
serum, incubated with primary antibodies at 4°C overnight, washed in PBS,
incubated with 1/1000 Alexa Fluor-488 or Alexa Fluor-594 conjugated secondary
antibody (Molecular Probe) for 1 hour at room temperature, washed in PBS,
mounted in glycerol/PBS. Digital images were obtained with a Zeiss microscope
(Axioskop 2). The primary antibodies used were Laminin (Sigma, L9393),
E-cadherin (Signal Transduction, C20820), WT1 (Santa Cruz, sc192), cleaved
Notch1 (val1744) (Cell Signaling, 2421), cleaved caspase 3 (Asp175) (Cell
Signaling, 9661). NCAM monoclonal antibody, developed by T. Jessell, and
TROMA1 monoclonal antibody, developed by P. Brulet, were obtained from the
Developmental Studies Hybridoma Bank.
Embryonic proliferation and apoptosis
Antibody to phosphorylated histone H3 (Upstate Biochemicals) was used to
detect mitotic cells (Wei et al.,
1999). TUNEL assay was performed as described
(Gavrieli et al., 1992
). All
sections were stained with methyl green to identify nucleated cells.
Four-hundred to 600 cells per section were counted and the proportion of
mitotic or apoptotic cells was determined as a fraction of the total number of
nucleated cells, four kidneys/stage/genotype, five sections/kidney were
counted.
Kidney organ culture and immunohistochemistry
Embryonic day 12.5 kidneys were isolated and cultured in MEM/F12 containing
10% fetal bovine serum on Millicell culture plate insert (Millipore) at the
medium/gas interface for 3 days. Kidneys were fixed in 2% paraformaldehyde for
10 minutes, then in 95% methanol for 15 minutes and washed in PBST
(phosphate-buffered saline 0.1 M, pH 7.4, 0.1% Tween 20). They were stained
whole-mount with anti-pan-cytokeratin (Sigma, C2562) and WT1 (Santa Cruz,
sc192) antibodies at 4°C overnight, washed in PBS, incubated with 1/1000
Alexa Fluor-488 or Alexa Fluor-594 conjugated secondary antibody (Molecular
Probe) for 2 hours at room temperature, washed in PBS, mounted in glycerol/PBS
and viewed under a Zeiss confocal microscope (LSM510).
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Results |
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We reported earlier that expression of the PSEN1 transgene was
able to rescue the somite patterning defect of the Psen1-null mice
(Qian et al., 1998).
Similarly, such transgene expression restored the somite structures that were
completely absent in PSEN-null embryos
(Fig. 1B)
(Donoviel et al., 1999
).
Presenilin rescue mutants were indistinguishable when compared with their
littermate controls prior to E12.5. At E13.5, the mutants were overtly similar
to their littermates, although they were slightly smaller in size, and this
difference became more dramatic over time
(Fig. 1B). The mutants could be
unambiguously identified because their eyes lacked pigmentation, a phenotype
that is the subject of a separate study.
The presenilin rescue mutants died within 2 hours of birth. Examination of the organs revealed that, at P0, the kidneys were dramatically smaller than that of the littermate controls (Fig. 1C), suggesting a defect in kidney development. Western blot analysis showed that the PSEN1 protein could be readily detected in control kidneys (Fig. 1D, lane 1,2). However, as it was not detectable in Psen1/Psen2/PSEN1 rescue mutant (Fig. 1D, lane 3), it suggests that the defect is due to the loss of presenilins and the mutant kidney is herein referred as PSEN-null.
Histological analysis at various stages of kidney development revealed that, at E12.5, the ureteric buds were readily identified and were surrounded by condensed mesenchyme in both the control and the PSEN-null kidneys (Fig. 2A,B, asterisks). This result suggests that the inductive interactions between the ureteric bud epithelium and the metanephric mesenchyme proceeded normally in the absence of presenilins. However, at E13.5, while the kidney development was further advanced in the control, as evidenced by the appearance of pretubular aggregates/renal vesicles (distinguished upon further analysis, see Fig. 4) and comma- and S-shaped bodies (Fig. 2C, thin arrow and arrowheads respectively), only pretubular aggregates/renal vesicles (Fig. 2D, thin arrow) could be found in the PSEN-null kidney but no comma- and S-shaped bodies were identified. This result indicates that presenilins play a critical role in the progression of pretubular aggregates/renal vesicles towards comma- and S-shaped bodies during nephrogenesis. Analysis of kidneys at later stages (E15.5 and P0) supports this view as mature glomeruli, which could be readily detected in the controls (Fig. 2E,G, thick arrows), were completely absent in the PSEN-null kidneys (Fig. 2F,H). The same kidney defect is present in another PSEN rescue line (17-3) (data not shown), and we therefore conclude that the phenotype is the result of the loss of presenilin expression rather than transgene integration.
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To exclude a possible contribution of stromal mesenchyme to the defects, we further evaluated stromal mesenchyme marker Bf2 expression and its levels were not significantly different in the mutants and controls (data not shown). Therefore, the combined data suggest that loss of presenilins does not disrupt the early inductive interactions and that the nephrogenic phenotype in PSEN-null kidney is probably due to a defect intrinsic to the mesenchyme.
Analysis of mesenchymal to epithelial cell conversion
The presence of mesenchymal condensates and aggregates but absence of
comma- and S-shaped bodies in PSEN-null kidney prompted us to examine the
mesenchyme to epithelium transition (MET). The neuronal cell adhesion molecule
(NCAM) is highly expressed only in mesenchymal derivatives, but not in the
ureteric buds. NCAM-positive structures (green) were readily detected in both
the control and PSEN-null kidney at E14.5
(Fig. 4A, parts a,b) and E16.5
(Fig. 4A, parts c,d). The
majority of NCAM-positive structures were also positive for pan-laminin
(Fig. 4A, red), which is found
in the basement membranes of both ductal and renal epithelia
(Cho et al., 1998). These data
suggest that the mesenchymal derivatives were competent for
epithelization.
The proper expression of laminin A chain has been shown to be crucial for
epithelial polarization (Ekblom et al.,
1990; Klein et al.,
1988
). Polarized, laminin
1-positive renal vesicles were
readily identifiable in PSEN-null kidney
(Fig. 4Bb, arrow). The
epithelial nature of these mesenchymal derivatives was further confirmed by
their positive staining for E-cadherin (present in both ductal and renal
epithelia, green) and negative for cytokeratin 8 (ductal epithelium only, red)
(Fig. 4C). These results
establish the notion that presenilins are not required for MET.
Analysis of nephron patterning
Detailed examination of NCAM-positive structures revealed that multiple
types were identified, including laminin-low irregular aggregates
(Fig. 4A, asterisks),
laminin-positive organized renal vesicles with lumen
(Fig. 4A, thin arrows), and
elongated laminin-expressing tubules (Fig.
4A, part d, thick arrow), suggesting that the pretubular
aggregates progressed into renal vesicles and tubules in PSEN-null mutant
kidney. Consistent with this assessment, the E-cadherin-positive renal
derivatives in PSEN-null mutant, similar to the littermate control, have
formed immature tubular structures which were either in close proximity
(Fig. 4C, part b, arrowhead) or
appear to have connected with the duct (thick arrows in d and arrowhead in f,
Fig. 4C). These characteristics
suggest the formation of distal tubules. However, in contrast to the control
in which advanced tubules with adjoining glomerular clefts could be recognized
(Fig. 4C, part e), the mutant
structures failed to undergo further differentiation and patterning.
To investigate a possible defect in proximal tubule development in the
PSEN-null kidney, we performed staining with Lotus Tetragonolobus lectin
(LTL), which is a specific marker for proximal tubules
(Cho et al., 1998). Remarkably,
although the control kidney showed strong staining with LTL
(Fig. 5A, parts a,c), no
positive staining could be detected with LTL in the mutant
(Fig. 5A, part b,d).
Immunostaining for WT1, which is highly expressed in the podocyte precursor
cells of S-shaped bodies and mature glomeruli
(Ryan et al., 1995
), revealed
a complete absence of WT1 expression in PSEN-null kidney as well
(Fig. 5B). Thus, presenilins
are absolutely required for the formation of proximal structures including
proximal tubules and glomeruli.
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Effect of proliferation and apoptosis during nephrogenesis
Analysis of cells undergoing active division with an anti-phosphorylated
histone H3 antibody showed that the cell proliferation profile was similar
between the mutant kidney and the control at both E13.5 (data not shown) and
E15.5 (Fig. 6A, parts a,b).
Double staining with the anti-NCAM (Fig.
6A, parts c,d) and cytokeratin 8 antibodies (not shown) indicated
that the proliferation rate of renal and ductal derivatives, respectively,
were also similar. However, we cannot rule out the possibility that minor
differences in cell proliferation in renal structures affected the tubule
growth and patterning in presenilin mutant. This finding is not unexpected
because much of the mesenchymal derivatives that required active cell division
have already formed in the PSEN-null kidney.
|
Using co-immunostaining to detect the activated form of caspase 3 and NCAM (Fig. 6B, parts c,d), we were able to evaluate the apoptotic profile of the renal structures. Similar to the control, pretubular aggregates and renal vesicles in PSEN-null exhibited no caspase 3 activity. However, high caspase 3 staining was observed in NCAM-positive tubular structures in the PSEN-null kidney (Fig. 6Bd, arrow). Similar to the TUNEL staining, cortical mesenchyme also showed higher caspase 3 activation (Fig. 6B, part d, arrowheads). Overall, our results suggest that defective patterning of immature distal tubules in the absence of presenilins leads to the attenuation of nephrogenesis and enhanced apoptosis.
Analysis of Notch pathway molecules in kidney development
Because an impaired Notch signal transduction is considered the leading
mechanism for the somite patterning defect of PSEN-null mice, we assessed the
expression of Notch pathway molecules in E14.5 PSEN-null kidneys. First, we
examined cell types exhibiting the presenilin -secretase activity by
immunostaining with an antibody that recognizes a PSEN-cleaved and activated
form of Notch1, the Notch intracellular domain (NICD)
(Fig. 7A). Co-staining with an
anti-cytokeratin 8 antibody (CK8) marked the ductal derivatives. NICD was not
expressed above background in ureteric bud epithelium in both the control and
PSEN-null samples (Fig. 7A). In
the control kidney, NICD immunoreactivity could be detected in pretubular
aggregates/renal vesicles (Fig.
7Aa), and comma- and S-shaped bodies (data not shown). PSEN-null
kidney was devoid of NICD although pretubular aggregates were present
(Fig. 7A, part b). Notch
activation was correlated with expression of its downstream target
Hesr1 (Hey1 Mouse Genome Informatics)
(Kokubo et al., 1999
) in the
control (Fig. 7B, part a). By
contrast, Hesr1 expression cannot be detected in PSEN-null mutant
(Fig. 7Bb), consistent with an
obligatory role of presenilins in Notch processing and signaling. The residual
signal probably results from staining of blood vessels that also express
Hesr1. These results support the idea that a presenilin-mediated
nephrogenic signal is derived from the mesenchyme, and that
presenilin-dependent Notch activation and signaling is the mechanism in
operation.
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In situ hybridization analysis of another Notch ligand, Dll1, showed that, in contrast to Jag1, Dll1 was not expressed in condensed mesenchyme or pretubular aggregates. Dll1-positive staining could be seen in comma- and S-shaped bodies in the control kidney (Fig. 7D, part a, arrowheads), but no Dll1 expression could be detected in the PSEN-null at any stages of nephrogenesis (Fig. 7D, part b). This negative staining could be attributed by the lack of Dll induction caused by defective Notch signaling or by the absence of comma- and S-shaped bodies in PSEN-null mutant kidney. It is interesting to note that Dll1 expression seems to be restricted to a specific region of comma- and S-shaped bodies (Fig. 7D, part a, arrowheads), although the fate of these cells is not clear. Similar to NICD and Hesr1, both Notch ligands were not expressed in the ureteric bud, again supporting a cell autonomous mechanism of presenilin-dependent Notch signaling within the mesenchyme.
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Discussion |
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Progression from pretubular aggregates to comma- and S-shaped bodies requires the conversion and patterning of mesenchymal cells into highly organized and polarized epithelia. Analysis of cell adhesion molecules and extracellular matrix proteins, NCAM and E-cadherin, revealed that renal vesicles and tubular derivatives were partially formed in the PSEN-null kidney. Importantly, laminin stained these renal structures suggesting that they developed polarized cells with basement membranes. Thus, presenilins are not essential in the mesenchyme to epithelium transition. However, despite the formation and apparent fusion of some E-cadherin positive distal renal tubule structures to the bud epithelium, mature proximal tubules and glomeruli were completely absent in PSEN-null kidney. This conclusion was supported by the negative binding to LTL and lack of expression of WT1, respectively. From these data, we conclude that presenilins play an indispensable role in the patterning and differentiation of renal vesicles leading to proximal tubules and glomeruli.
In contrast to inductive interactions and MET, our current understanding
about nephron patterning is limited. There are candidate regulatory mechanisms
in tubule patterning by molecules such as the cadherins, which are
differentially regulated in the various renal epithelial compartments
(Cho et al., 1998). However,
gene knockout studies have not supported a clear function of these molecules
in nephron patterning (Dahl et al.,
2002
; Dressler,
2002
; Mah et al.,
2000
). The presenilins represent one of the first examples of
molecules that play an essential role in patterning and differentiation of
renal vesicle derivatives.
Role of presenilins in Notch signaling during nephrogenesis
Presenilins are indispensable for the processing and signaling of Notch.
This activity is highly conserved and likely accounts for the role of
presenilins during somite patterning
(Donoviel et al., 1999;
Takahashi et al., 2000
). Our
analysis showed that the presenilin
-secretase activated form of Notch1
(NICD), Notch downstream target Hesr1 and ligands Dll1 and
Jag1 were expressed in mesenchymal derivatives and that their
expressions were critically impaired in PSEN-null kidneys. Thus, the Notch
pathway, particularly signaling through Notch1, may be the underlying mediator
for presenilin activity in kidney development. It is noteworthy that mice
expressing a hypomorphic allele of Notch2 exhibit kidney
glomerulogenesis defects (McCright et al.,
2001
). As all four mammalian Notch proteins are presenilin
substrates in vitro (Saxena et al.,
2001
), a defective Notch2-mediated pathway may also account for
the PSEN-null kidney phenotype. However, the presence of glomeruli in Notch2
mutant kidneys, albeit structurally abnormal, indicates that Notch2 functions
downstream of tubule patterning (McCright
et al., 2001
).
Although an essential role for the presenilins in Notch signaling has been
well established, how this regulation affects Notch ligand expression has been
the subject of controversy. Some support a lateral inhibition model in which
loss of Notch signaling resulting from presenilin deficiency leads to ectopic
overexpression of the ligand (Donoviel et
al., 1999; Handler et al.,
2000
); Others suggest that presenilin-mediated Notch signaling is
necessary for proper induction of its ligand
(Takahashi et al., 2000
). The
differences may be caused in part by variations of the systems of study; as
ligand expression seems to be subjected to strict temporal-, spatial- and cell
type-specific regulation.
In kidney development, detailed examination of expression patterns of Jag1 and Dll1 yielded some interesting findings.
(1) Jag1 is not expressed in condensed mesenchyme but its expression can be detected in pretubular aggregates and renal vesicles. This distinct Jag1 staining pattern was similar in the control and the PSEN-null kidneys at E14.5, suggesting that transition from condensed mesenchyme to pretubular aggregates does not depend on presenilins. Interestingly, although pretubular aggregates and renal vesicles still exist in PSEN-null mutant at E16.5, Jag1 expression is lost. These data suggest that sustained Notch activation is necessary for the maintenance of Jag1 expression during nephrogenesis.
(2) In contrast to Jag1, Dll1 message cannot be detected in
pretubular aggregates. In the control kidney, Dll1 expression seems
to be restricted to a specific region of the comma- and S-shaped bodies at
E14.5. Although the origin of these cells is not known, this spatiotemporally
restricted expression pattern may imply functional significance. Indeed,
during somite patterning, caudally restricted expression of Dll1 has
been shown to be important for prefiguring somite identity, and proper
Dll1 induction requires presenilin-dependent Notch signaling
(Takahashi et al., 2000).
Equally possible, however, the absence of Dll1 expression could also
be due to the physical lack of comma- and S-shaped bodies in the PSEN-null
kidney.
Besides Notch and APP, numerous other proteins have been reported as
substrates of presenilin-dependent proteolysis
(Lammich et al., 2002;
Marambaud et al., 2002
;
Ni et al., 2001
). Although the
physiological significance is not clear, impaired processing of these
molecules cannot be excluded as a potential mechanism for the kidney defects.
Through processing-independent mechanisms, PSEN1 has been shown to interact
with ß-catenin and to facilitate its turnover
(Kang et al., 2002
;
Xia et al., 2002
). Therefore,
it is possible that deregulation of the ß-catenin pathway in the
PSEN-null may contribute to the kidney phenotype. The Wnt pathway has been
implicated in the inductive phase of kidney development
(Dressler, 2002
), but is
essentially unaffected in the PSEN-null. In addition, we have created mice
with a deletion of exon 10 of the endogenous Psen1 essential for
ß-catenin interaction. Homozygous exon 10-deleted mice, when crossed onto
the Psen2-null background, are viable and do not exhibit kidney
defects (H.Z., unpublished). These observations thus argue against a potential
ß-catenin involvement in the PSEN-null kidney.
In addition to the kidney patterning defect, Psen1- and
Psen2-double null embryos display other abnormalities, most
noticeably defects in heart looping and vascular remodeling
(Donoviel et al., 1999;
Herreman et al., 1999
). These
defects were apparently corrected by the human PSEN1 transgene
presumably because of its early expression in mesoderm and in relevant cell
derivatives. Indeed, the human Thy-1 promoter has been shown to be active in
endothelial cells (Gordon et al.,
1987
), and expression of Hesr1, although absent in
developing nephrons of the PSEN-null kidney, can be detected in blood vessels.
The analysis of mechanisms leading to these phenotypes is currently
ongoing.
In summary, using our novel presenilin `rescue' system, we have identified a novel function of the presenilins in nephrogenesis. Specifically, presenilins are indispensable for the patterning of renal epithelial structures to form mature proximal tubules and glomeruli. Loss of presenilins is associated with failed progression from renal vesicles to comma- and S-shaped bodies. On the molecular level, we reveal an obligatory role of presenilins in the activation of Notch signaling and maintenance of the Notch ligand Jag1 expression in the mesenchymal derivatives during kidney development.
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ACKNOWLEDGMENTS |
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