1 Department of Experimental Medicine I, University Erlangen-Nürnberg,
91054 Erlangen, Germany
2 Department of Ophthalmology, University Erlangen-Nürnberg, 91054
Erlangen, Germany
3 Department of Molecular Biology and Biochemistry, Okayama University Medical
School, Okayama 700, Japan
4 Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences,
University of Manchester, Manchester M13 9PT, UK
* Author for correspondence (e-mail: epoeschl{at}molmed.uni-erlangen.de)
Accepted 12 December 2003
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SUMMARY |
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Key words: Collagen IV, Col4a1, Col4a2, Knockout, Basement membrane, Development
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Introduction |
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Basement membranes comprise specialized matrix components from different
protein families (Timpl,
1996). Laminins are a family of at least 15 distinct
heterotrimeric molecules, which form gel-like aggregates
(Colognato and Yurchenco,
2000
). Nidogen-1 and -2 mediate the formation of ternary complexes
between laminin and collagen IV in vitro
(Fox et al., 1991
;
Kohfeldt et al., 1998
), but
their significance in vivo is not yet fully defined
(Murshed et al., 2000
;
Schymeinsky et al., 2002
).
Heparan sulfate proteoglycan perlecan is integrated into the networks of
laminins and collagen IV and plays important roles in the maintenance of
basement membrane integrity, its filtration functions and also the local
storage of growth factors (Göhring et
al., 1998
). More complexity may be inferred from the
identification of new isoforms of known molecules and discovery of additional
specialized proteins (Erickson and
Couchman, 2000
).
So far, the analyses of human diseases and knockout animal models have
defined distinct functions of the various basement membrane components for its
overall integrity and function. For example, tissue-specific defects at
various stages of development are caused by the lack of perlecan
(Costell et al., 1999), by
mutations within any of the genes coding for laminin-5 chains (
3,
ß2,
2) (Pulkkinen and Uitto,
1999
), the laminin
2 chain
(Helbling-Leclerc et al.,
1995
) or by the disruption of the laminin
5 gene
(Miner et al., 1998
). However,
only the targeted inactivation of the laminin
1 chain resulted in the
lack of basement membranes due to the ablation of 10 out of the 14 currently
known laminin isoforms, causing mutant embryos to die at E5.5 from early
differentiation defects (Smyth et al.,
1999
). The complexity of contributions of individual proteins to
in vivo functions and their mutual interactions is further illustrated by the
targeted deletion of the highly specific binding site of nidogen-1 on the
laminin
1 chain causing local disintegration of basement membranes,
which leads to renal agenesis and impaired lung development
(Willem et al., 2002
). In
contrast, the corresponding ablation of nidogen-1 or -2 resulted in no obvious
phenotypes (Murshed et al.,
2000
; Schymeinsky et al.,
2002
). Although the differential expression of components by
neighboring cells (Ekblom et al.,
1994
; Thomas and Dziadek,
1993
) and the central role of matrix receptors in coordinating the
spatial and temporal aggregation of basement membranes
(Henry and Campbell, 1998
;
Li et al., 2002
) has shed new
light on the molecular mechanisms of the supramolecular assembly of basement
membranes, the contributions of individual proteins is not yet fully
understood.
Members of the collagen IV family
(Kühn, 1995) are found in
all basement membranes and are characterized by their ability to form complex,
covalently linked structural scaffolds, proposed to be required for the
basement membrane assembly process (Timpl
et al., 1981
; Yurchenco and
Furthmayr, 1984
). Six individual chains have been identified,
1(IV)-
6(IV), which assemble into three distinct protomers,
1.
1.
2(IV),
3.
4.
5(IV) and
5.
5.
6(IV) (Boutaud et
al., 2000
; Hudson et al.,
2003
). In addition to the ubiquitous
1/
2 network,
two independent networks,
3.
4.
5(IV) and a combined
aggregate of
1.
1.
2/
5.
5.
6(IV)
molecules, have been described (Borza et
al., 2001
). They are deposited later in development and replace
the initial
1.
1.
2(IV) network in a tissue-specific manner
and define specialized basement membrane structures and functions. The
3.
4.
5(IV) network is found in the glomerular basement
membrane and some tubules of the kidney, in the lung, testis, cochlea and eye,
whereas the
5.
5.
6(IV) protomer is detected in the skin,
esophagus, Bowman's capsule of the kidney and smooth muscle cells
(Ninomiya et al., 1995
).
Therefore, mutations in any of the genes coding for the
3(IV)-
5(IV) chains cause tissue-specific phenotypes, associated
with different forms of the Alport's syndrome
(Hudson et al., 2003
;
Tryggvason, 1996
) or related
diseases (Badenas et al., 2002
;
Buzza et al., 2001
). Yet, no
genetic defects in either the
1(IV) or
2(IV) chains have been
linked to human diseases so far, while mutations of collagen IV related genes
in Drosophila melanogaster or Caenorhabditis elegans lead to
embryonic lethal phenotypes (Borchiellini
et al., 1996
; Gupta et al.,
1997
). The
1.
1.
2(IV) isoform is detected in
the mouse embryo at the 32-64 cell stage
(Dziadek and Timpl, 1985
) and
is therefore thought to be of crucial importance for the formation of the
first sheet-like structured basement membrane in development. Together, these
data support a fundamental role for the major collagen IV isoform during
development.
We have defined for the first time the functional significance of the major
collagen IV isoform 1.
1.
2(IV) in vivo by the targeted
inactivation of the Col4a1/2 locus in mice. Surprisingly, deposition
of basement membrane components was not dependent on the presence of collagen
IV during early embryonic development and embryonic lethality occurred only at
E10.5-11.5 because of impaired basement membrane stability. These data suggest
therefore that collagen IV is not critically important for the formation of
basement membrane-like matrices, but is indispensable for structural integrity
and functions of basement membranes at later stages.
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Materials and methods |
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Generation of a mouse strain with deficient Col4a1/2 locus
Two independent clones (1D2, 11D3) with correct integration were injected
into C57BL/6 blastocysts and transferred into pseudopregnant CD1 foster
mothers. Highly chimeric males were obtained and crossed with C57BL/6 females
to obtain heterozygous F1 offspring. Genotyping was done as
described above or by PCR using the primers Col4a2-Ex2dw
(5'-GTTAGGAAGGGATCGAGC), Hind+104up (5'-ACCACCTCTGAGTTTCTGGA) and
Neodw (5'-TCGTGCTTTACGGTATCGCC), resulting in fragments of 597 and 650
bp for the wild-type and mutant alleles, respectively. Heterozygous mice were
mated to obtain time-staged embryos.
Histological analysis and immunohistochemistry
E9.5-E11.5 embryos were dissected, fixed for 2-4 hours in 4% (w/v)
paraformaldehyde in PBS and then embedded in paraffin wax, sectioned (5-10
µm) and stained using Hematoxylin-Eosin or Periodic acid-Schiff reaction
according to standard methods. For immunostaining, tissues were snap-frozen in
OCT and cryosections (7-12 µm) were transferred to silanized slides.
Immunostaining was performed with polyclonal antibodies to nidogen-1,
laminin-1 recognizing isoforms containing 1, ß1 and
1
chains and collagen IV (Fox et al.,
1991
). Monoclonal antibodies (H12, H22 and H53) were generated
against the individual collagen IV subunits
1(IV),
2(IV) and
5(IV), respectively (Sado et al.,
1995
). Commercially available collagen IV antibodies (Chemicon
Int.), PECAM-1 (Pharmingen) and Cy2- or Cy3-conjugated secondary antibodies
(Dianova) were used.
Ultrastructural analysis
Tissue specimens were fixed in 2.5% glutaraldehyde in 0.1 M phosphate
buffer (pH 7.4) for 24 hours at 4°C, postfixed in 1% buffered osmium
tetroxide, and routinely processed for embedding in epoxy resin (EPON 812) and
transmission electron microscopy (LEO 906E, Oberkochen; Germany).
Detection of collagen IV specific mRNA
Total RNA was isolated from E9.5 and E10.5 littermate embryos using Trizol
(PEQ-Lab). Collagen IV-specific mRNAs were detected after reverse
transcription using random primers (Roche) by PCR amplification using
cDNA-specific primers (20 bases, Tm 58°-60°C) amplifying fragments
according to database entries specific for 1(IV) (a1N:
MUSCOL4A1/J04694, pos. 272-613, 342 bp),
2(IV) (a2N: MUSCOL4A2/J04695;
pos. 92-260; 169 bp),
5(IV) (a5N: AB041350; pos. 4858-5139; 282 bp) or
annexin A5 (Anxa5: MUSANXV/D63423; pos. 51-242; 192 bp) as internal controls
(Fig. 1). Quantitative PCR
analyses (Fig. 4) were
performed in a thermal cycler equipped with a real-time fluorescence detector
(iCycler, BioRad) and the AbsoluteTM QPCR SYBR Green Mix (ABgene) was
used according to the suppliers protocols. The primers (18-20 bases; Tm
58°C) were selected from published sequences (GenBank) to amplify cDNA
fragments specific for
1(IV) and
5(IV) as given above, as well
as for
2(IV) (MUSCOL4A2/J04695, pos. 92-200, 109 bp),
3(IV)
(AF169387, pos. 4678-4832, 155 bp),
4(IV) (AF169388, pos. 4672-4881,
210 bp),
6(IV) (AB041351, pos. 4570-4876, 307 bp), laminin
1
chain (NM_008480, pos. 5011-5257, 247 bp), nidogen-1 (NM_010917, pos.
3889-4036, 148 bp) and GAPDH (NM_008084, pos. 581-1023, 443 bp).
PCR-amplifications were performed in triplicates with 50 cycles at an
annealing temperature of 58°C. The iCycler analysis software (BioRad) was
used for data analysis and the amounts of products were calculated from
standard curves generated in parallel from dilutions of each PCR products.
Data were normalized to the levels of GAPDH-specific cDNA set as 100%.
Calculation of mean values and standard deviations were based on triplicate
assays, analyses were repeated three times and representative results are
shown. Specificity of PCR products was tested by measurement of Tm-value and
gel electrophoresis after 50 cycles.
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Results |
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Heterozygous mice appeared normal and did not display overt anatomical or behavioral abnormalities. However, no mice homozygous for the mutation could be identified after weaning, indicative of an embryonic lethal phenotype (Table 1). Surprisingly, genotypes of time-staged embryos showed no significant deviation from normal Mendelian ratio up to E9.5, but thereafter a steady decrease of homozygous mutants demonstrated embryonic lethality between E10.5-E11.5. In parallel an increase in disintegrated or resorbed embryos was seen. Occasionally, homozygous mutants were found at E11.5, but embryos never survived beyond E12. Collagen IV-deficient embryos showed no or only marginal changes in overall size and body shape at E9. However, a variable degree of growth retardation was observed at E9.5-E11 for many of the mutant embryos (Fig. 2). In most cases the smaller size was not linked to a significantly reduced number of somites. Occasionally, some mutant embryos were severely developmentally retarded and corresponded to stages 12-36 hours earlier, when compared to their normal littermates. Organ development was similar to controls and all living collagen IV-deficient embryos had a beating heart. In addition, chorio-allantoic fusion had taken place and development of extra-embryonic structures, such as yolk sac and amnion showed no obvious structural defects (not shown). Together, these data demonstrate that early embryonic development and organogenesis occurs normally in the absence of collagen IV.
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Deficiency of collagen IV results in altered basement membrane structures
Although immunofluorescence analysis clearly demonstrated the presence of
basement membrane-like structures in mutant embryos, the staining looked more
patchy and appeared weaker when compared to littermate controls
(Fig. 3). In addition,
discontinuities or ruptures of basement membranes were apparent both in mutant
embryos (Fig. 3A) and in
extraembryonic tissues (Fig.
3B). The most obvious changes were visible in the specialized
Reichert's membrane underlying the parietal endoderm cells. It is normally
formed from typical basement membrane matrix proteins such as collagen IV,
laminins, nidogens and perlecan, and defines a stable barrier between parietal
endoderm cells and the trophoblast layer
(Fig. 5A). In the mutants,
however, it appeared fragile, thin or disorganized and breaches in the
basement membrane were visible in many places. As a consequence, excessive
amounts of maternal blood were found in the yolk sac cavity
(Fig. 5A), which may be one of
the major reasons leading to death and resorption of mutant embryos.
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No gross abnormalities in organ development or tissue structures were observed in collagen IV-deficient embryos, but indications of an increased instability of basement membranes was detected in various tissues. In the brain, neuronal ectopias were apparent in embryos at E11.5 (Fig. 6), characterized by cells protruding into the surrounding mesenchyme. Local disruption of the pial basement membrane (see Fig. 8) is most probably the reason for the aberrant migration of neural cells.
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Reduced thickness and an aberrant internal structure of basement membranes was most obvious in the Reichert's membrane (Fig. 8C). While this thick basement membrane had a homogenous appearance in normal embryos, electron-dense string-like structures in a loose and irregular arrangement were evident in the mutants. We speculate that these structures reflect a modified supramolecular organization of components in the absence of the stabilizing collagen IV network that becomes visible after fixation of specimens. At many sites also the contact with the trophectoderm layer and parietal endoderm cells was lost and again suggests defects in cell-matrix interactions.
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Discussion |
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The presence of basement membrane-like matrices in the absence of the major
collagen IV isoform 1.
1.
2(IV) shows that the secretion
and deposition of other basement membrane proteins is sufficient to provide
the essential functions of basement membranes during early development. The
ability of laminin to form gel-like aggregates in vitro in the presence of
calcium ions (Yurchenco and Cheng,
1993
) suggests that minimal matrices, containing laminins as major
structural components, are sufficiently stable to form laminar structures and
enable differentiation, proliferation and survival of cells. The hypothesis
that only laminins are crucial during early development is supported by the
fact that the deletion of the laminin
1 chain caused fatal consequences
during the peri-implantation period (Smyth
et al., 1999
), but not the ablation of any other basement membrane
component analyzed so far (Costell et al.,
1999
; Murshed et al.,
2000
; Schymeinsky et al.,
2002
). However, there is currently no ultimate model available to
describe the molecular organization of basement membrane components in early
embryos. It remains therefore open at present whether laminins alone are
sufficient or whether any other basement membrane component is required for
its stabilization. The absence of single components, like nidogens, perlecan
or even collagen IV may be tolerated to form minimal basement membrane-like
matrices that support at least some basic functions.
The major basement membrane components are correctly deposited, suggesting
that the absence of collagen IV does not negatively regulate secretion or
deposition of laminins, nidogens or perlecan. Occasionally, we observed a
weaker staining intensity in mutants, which may be due to a decreased
synthesis. We favor, however, the idea that this effect is based on a reduced
retention of basement membrane components into a complex supramolecular
aggregate in the absence of the covalently stabilized collagen IV network. A
similar finding has been observed in mice lacking the nidogen-binding module
of the laminin 1 chain, in which nidogen was not retained in basement
membranes despite normal protein amounts
(Willem et al., 2002
).
The development of embryos up to E10-E11 demonstrates that the collagen
1.
1.
2(IV) network is not crucial for blastocyst
formation, maturation, implantation and initial morphogenetic events. The
constraints on the intrinsic stability of basement membranes to maintain its
barrier functions increase gradually in the embryo during progressive
proliferation of cells and the differentiation and expansion of cell layers.
Therefore, the observed local disintegration of basement membranes in collagen
IV-deficient embryos later in development is probably due to reduced stability
of matrix aggregates. One example is the vascular bleeding in the heart and
arteries as the cell-cell contacts are not sufficient to stabilize the tissue
architecture. A second example is the fracture of the Reichert's membrane and
accordingly, insufficient barrier between maternal and embryonic environments
causes excessive bleeding into the yolk sac cavity and resorption of embryos.
The loss of barrier function is also reflected in the development of neuronal
ectopias in E11.5 mutant embryos because of the local disintegration of the
basement membrane separating the embryonal neuroectoderm from the surrounding
mesenchyme. Similar cortical defects have been described for mice lacking
perlecan, mutations inhibiting the laminin-nidogen interaction or upon
inactivation of cell surface receptors
(Costell et al., 1999
;
Georges-Labouesse et al.,
1998
; Graus-Porta et al.,
2001
; Halfter et al.,
2002
; Moore et al.,
2002
). These defects cause fragmented pial basement membrane
between E10.5-12.5 (Halfter et al.,
2002
) through which Cajal Retzius cells and other neuronal cells
migrate into the surrounding mesenchyme. Together, these phenotypes support
the notion that collagen IV has an essential role to maintain the structural
integrity of basement membranes at stages associated with increasing
mechanical demands. Yet, we cannot exclude, at the moment, the possibility
that impaired cell-matrix interactions cause the detachment of basement
membranes from underlying cell layers and contributes to the observed
phenotypes. Loss of cell-matrix contact, as seen at many sites, could also be
an explanation for the gradual increase of growth retardation preceding the
lethality around E10-E11 and it may influence proliferation and
differentiation of cells. Alternatively, impaired placental development and
the observed local distortion of the capillary networks may decrease nutrition
of the embryos.
Although basement membrane-like deposits formed in collagen IV-deficient
embryos, they showed distinct differences to those of controls in
ultrastructural analysis. Reduced thickness, discontinuities, amorphous
deposits or loss of any matrix deposits were seen. In contrast to the
homogenous appearance of matrix in normal embryos, electron-dense, irregular
aggregates were detected in the absence of collagen IV. A similar
ultrastructure was seen before in a cell line known to secrete a collagen
IV-free basement membrane-like matrix
(Brauer and Keller, 1989).
Therefore, we propose that the altered supramolecular architecture of basement
membranes in the absence of collagen IV results in the formation of aberrant
aggregates. Mutations of collagen IV-related genes cause embryonic lethality
in invertebrates. Reduced expression of the collagen IV-related gene
Dcg in Drosophila
(Borchiellini et al., 1996
) and
null mutations in collagen IV chain homologues emb-9 and
let-2 in Caenorhabditis resulted in failure of basement
membrane structures and finally caused embryonic lethality because of the lack
of functional muscle attachment sites
(Gupta et al., 1997
). Although
it was surprising that corresponding mutants in mouse embryos are able to
develop up to E10-E11, the residual functionality of collagen IV-deficient
basement membranes seems to be sufficient for basic functions and enable early
embryonic development.
In contrast to invertebrates, mammals contain multiple collagen IV isoforms
and the consequences of mutations in collagen IV variants reflect the pattern
of expression and specific basement membrane functions. Mutations of the
COL4A3-COL4A6 genes in humans are associated with various forms of
Alport's related syndromes (Gunwar et al.,
1998; Hudson et al.,
2003
; Kashtan,
2000
; Tryggvason,
1996
). During development the ubiquitous collagen IV network,
1.
1.
2(IV), is replaced in a tissue- and stage-specific
manner by the minor isoforms and it is believed that the local expression of
these chains restricts the impairment of basement membrane function to organs
expressing these chains, such as kidney or lung. The detection of basement
membrane-like structures in the absence of the major collagen IV isoform
1.
1.
2(IV) may be compensated for by the presence of
3(IV)-
6(IV) chains, which may assemble into two distinct
protomers,
3.
4.
5(IV) or
5.
5.
6(IV)
(Boutaud et al., 2000
).
However, immunostaining for distinct collagen IV chains did not reveal
significant amounts of
3(IV)-
6(IV) chains in wild-type embryonic
basement membranes or in mutant embryos. By quantitative RT-PCR we could only
detect trace amounts of
3(IV),
4(IV) and
6(IV) mRNAs in
normal and mutant embryos. Therefore, no significant amounts of any
heterotrimeric collagen IV protomer can be assembled and secreted in mutants
and monomeric
5(IV) chains are only found intracellularly. These data
suggest that collagen IV aggregates are dispensable for the deposition of
basement membrane-like structures during early embryonic development. However,
it remains to be analyzed how the
1.
1.
2(IV) deficiency
influences the tissue-restricted formation of the mixed
1.
1.
2/
5.
5.
6(IV) network later in
development.
Interestingly, the phenotype of collagen IV-deficiency shows some
similarity to the targeted inactivation of the collagen-specific chaperone
Hsp47 (Nagai et al., 2000).
These mutant mice died before E11.5, the secretion of processed collagen IV,
as well as collagen I, was reduced and defective basement membrane structures
were also observed. As inactivation of only collagen I causes embryonic
lethality at E13.5 because of ruptures of major blood vessels and mesenchymal
necrosis (Harbers et al.,
1984
; Lohler et al.,
1984
), we speculate that the phenotype of Hsp47-deficient mice
mimics in some aspects that of collagen IV-deficient embryos described here.
Additional phenotypes in Hsp47-deficient embryos, such as formation of
aberrant epithelia and the disruption of blood vessels, may be explained by
the chaperone functions of Hsp47 on the formation of stable protomers of other
members of the collagen family.
Based on the data presented, we propose that deficiency of collagen IV has
no, or only a limited, influence on the deposition and function of basement
membrane-like structures during early development. Recently, it was proposed
that the secretion of laminins and their recruitment by specific cellular
receptors like ß1-integrins or dystroglycan, represents the first crucial
step for basement membrane formation (Li
et al., 2002). The local concentration of deposited laminins would
thus enable their efficient assembly into gel-like aggregates in the presence
of calcium ions (Yurchenco and Cheng,
1993
; Yurchenco and Cheng,
1994
). Such laminin-based minimal matrices could provide the
flexibility and variability that is necessary for the differentiation and
proliferation of cells when mechanical demands on the integrity of basement
membranes are limited. However, the presence of specific collagen IV networks
is essential for the intrinsic cohesiveness of basement membranes under
conditions of increasing mechanical demands and the formation of stable and
functional basement membranes.
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ACKNOWLEDGMENTS |
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