1 Institute of Molecular Biology, University of Zurich, 8057, Switzerland
2 Neuroscience Center, 8057, Zurich, Switzerland
3 Institute of Zoology, University of Zurich, 8057, Switzerland
* Author for correspondence (e-mail: michael.hengartner{at}molbio.unizh.ch)
Accepted 17 August 2005
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SUMMARY |
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Key words: Axon guidance, C. elegans, Cell migration, Heparan sulfate proteoglycan, Syndecan
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Introduction |
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HSPGs consist of a secreted or membrane-anchored protein core to which
several heparan sulfate (HS) polysaccharide chains are attached
(Bernfield et al., 1999;
Esko and Selleck, 2002
;
Lindahl et al., 1998
). Once
the HS chain is synthesized, specific enzymes including
sulfotransferases and an epimerase modify the individual sugar
moieties, resulting in complex modification patterns
(Lindahl et al., 1998
). A
complete lack of HS abrogates multiple signaling pathways essential for early
development, resulting in severe patterning defects and lethality
(Inatani et al., 2003
;
Bornemann et al., 2004
;
Herman et al., 1999
;
Morio et al., 2003
;
Perrimon and Bernfield, 2000
).
Together with the biochemical studies, these observations led to the
hypothesis that HSPGs act as co-receptors that bind and sequester
extracellular signals in the extracellular matrix
(Bernfield et al., 1999
;
Perrimon and Bernfield,
2000
).
By contrast, genetic removal of enzymes that secondarily modify HS,
including sulfotransferases and an epimerase, demonstrated that specific
modifications are needed for distinct axon guidance choices
(Bülow and Hobert, 2004).
Hence, it has been proposed that individual HS modifications in a given area
or on specific neurons give rise to a `sugar code' that regulates axon
guidance by modulating specific receptor-ligand interactions. So far it is not
known, however, which core proteins are crucial in this process and how they
function to modulate axon guidance signaling. Syndecans and glypicans are the
two major families of cell surface-bound HSPGs
(Fig. 1A). In mice, the
inactivation of a single syndecan gene does not result in any obvious
phenotype, probably due to redundancy between the family members
(Hartmann and Maurer, 2001
;
Bernfield et al., 1999
).
Syndecan mutant flies display a Robo-like midline phenotype, which can be
rescued by overexpression of either syndecan or the two Drosophila
glypican genes dally and dally-like
(Johnson et al., 2004;
Steigemann et al., 2004
).
Furthermore, it was found that lack of syndecan affects the distribution of
the midline repellent Slit, which provides the first indication of how HSPGs
might function (Johnson et al.,
2004
).
Unlike mammals, which have four syndecan family members, the Caenorhabditis elegans genome contains one single syndecan (core) gene. We show here that syndecan SDN-1 functions autonomously in neurons to ensure correct cell migration and axon guidance. Epistasis analysis indicates that signaling pathway, which acts in parallel with a second, currently unknown, guidance system that relies on a different combination of sugar modifications on a distinct HSPG protein. We therefore propose that at least two distinct HSPG patterns are involved in regulating axon pathfinding and cell migration.
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Materials and methods |
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Constructs
The Psdn-1::sdn-1::gfp translational fusion construct
pAH40 was generated by ligating a 5.7 kb BamHI-SphI fragment
covering 2.8 kb of 5' regulatory sequences and the entire coding region
into the pPD95.75 vector (gift of A. Fire, Stanford University), such that the
full-length sdn-1 open reading frame was fused in frame to
gfp. pAH40 and the lin-15 rescuing plasmid pL15EK (gift of
R. Horvitz) were co-injected (100 ng/µl of each) into
lin-15(n765ts) animals to, obtain transgenic lines. Two independent
lines (opIs170, opIs171) showed similar expression patterns.
Psdn-1::sdn-1 (pAH46) was made by cloning a 6.9 kb
genomic PCR product containing 2.8 kb of 5' sequences, the entire
sdn-1 coding region and the predicted 3'UTR into the pGEM-T
vector. The Pdpy-7::sdn-1(cDNA) construct was generated by
fusion PCR (Hobert, 2002): the
hypodermal promoter of dpy-7 (216 bp)
(Gilleard et al., 1997
) was
fused to the ATG start codon of the sdn-1 cDNA. The
Psra-6::sdn-1 plasmid (pCR1) and the
Punc-119::sdn-1 plasmid (pCR2) were made by subcloning the
sra-6 promoter (3747 bp) or the unc-119 promoter (2189 bp)
sequence into pPD95.86 (gift of A. Fire, Stanford University), in front of the
ATG start codon of the sdn-1 cDNA. For rescue, worms were injected
with 20 ng/µl of pAH46, pCR1 or pCR2, or with 2.5 ng/µl of the fusion
construct Pdpy-7::sdn-1. Constructs were injected together
with pTJ1157 (lin-48::gfp) and pBluescript SK at 50 ng/µl each,
or, for the rescue of HSN migration, with pPD118.33 (myo-2::gfp) at
2.5 ng/µl.
Isolation of the sdn-1 deletion allele
The sdn-1(zh20) deletion mutant was isolated from an
EMSmutagenized library consisting of approximately 106 haploid genomes, as
previously described (Jansen et al.,
1997; Berset et al.,
2001
). DNA pools were screened by nested PCR with the outer
primers OAH40 (5'-TGGGTTCATCCAATGCGTATGACC-3') and OAH49
(5'-CCCTATTCTGTCATTGTACCAC-3'), and the nested primers OAH41
(5'-TTGCCGTACACCGCCATTTCCTC-3') and OAH48
(5'-AGAATGGCTGTAATCACCGCAACG-3'). The zh20 deletion
removes 1260 bp within the coding region
(Fig. 1B). The sequence of the
break point is as follows: TTTGCTTCACAC//zh20//GTCGACAGGCAG. The mutant strain
was backcrossed six times to N2 before analysis.
Phenotypic analysis
All mutant alleles were backcrossed at least four times before phenotypic
analysis. Axon guidance defects were scored in staged young adults or L1
larvae using a Leica DMR microscope. Migration of HSN, ALM and CAN neurons and
coelomocytes were scored in adult stages (HSN, ALM, CAN) and L3-L4 stages
(coelomocytes).
Statistical analysis
All phenotypes, except defects in guidance and left/right choices of D-type
motoneurons (Fig. 6A), were
scored as the percentage of animals that were defective, and are shown with
error bars denoting the standard error of proportion. Statistical significance
was calculated using the z-test. For the defects in D-type motoneurons, error
bars give the standard error of the mean and statistical significance was
calculated by using Student's t-test. If multiple comparisons were
made, Bonferroni's correction was applied.
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Results |
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To study the role of SDN-1 in nervous system development, we first isolated a null allele of sdn-1. The deletion allele sdn-1(zh20) removes most of the sdn-1 open reading frame (Fig. 1B). Furthermore, no sdn-1 transcripts were detected on northern blots of RNA isolated from zh20 animals (Fig. 1C). Thus, the sdn-1(zh20) allele most likely causes a complete loss of SDN-1 function. Homozygous sdn-1(zh20) animals are viable, but they show defects in backward locomotion, are variably egg-laying defective and have a slightly reduced brood size (201±42, n=10) when compared with wild-type worms (280±10, n=10).
A recent study carried out with a hypomorphic allele of sdn-1
reported a role of SDN-1 in vulva development, but did not analyze neuronal
phenotypes (Minniti et al.,
2004). This published allele, sdn-1(ok449), results in an
in-frame deletion and produces a truncated form of SDN-1 lacking the two major
conserved HS attachment sites in the extracellular domain
(Fig. 1B). The truncated SDN-1
core protein in ok449 animals could still be detected on western
blots by using an antibody directed against the cytosolic tail, but was no
longer recognized by a monoclonal antibody specific for HS side chains,
indicating that there is considerably less, if any, HS attached to SDN-1 in
this mutant (Minniti et al.,
2004
). We examined the neural phenotypes of both sdn-1
mutants, but focused our epistasis analysis on the null allele
sdn-1(zh20), because the ok449 deletion may not completely
eliminate sdn-1 function (Table
1).
|
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Finally, we detected a cell migration defect of the macrophage-like coelomocytes, a non-neural cell-type. In wild-type hermaphrodites, four coelomocytes are born and migrate posteriorly during embryogenesis, whereas the two coelomocytes generated in the L1 stage do not migrate (Fig. 2F). In sdn-1(zh20) null mutants, the embryonic coelomocytes were often located too far anteriorly, just behind the pharynx (Fig. 2H). In all the cell migration events examined, SDN-1 always appeared to confer a pro-migratory property, irrespective of the direction of cell migration.
|
HSN motoneurons
In contrast to most axons, which join the VNC in the head or the tail, the
axons of the HSN neurons join the VNC midway near the vulva and grow
anteriorly without crossing the midline
(Fig. 3G,H). In
sdn-1(zh20) animals, HSN axons frequently crossed the midline
(Fig. 3I). As mentioned before,
the HSN neurons frequently fail to migrate to their normal position in
sdn-1 mutants (Table
1). To determine whether the misplacement of the HSN cell bodies
might contribute to the observed guidance defects, we scored HSN pathfinding
in animals with wild-type and misplaced HSN neurons separately
(Fig. 3I,
Table 1). We found that
crossover defects occurred in both cases, but were indeed more frequent in
animals with mispositioned HSN cell bodies.
|
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SDN-1 is highly expressed in the nervous system
In order to examine the expression pattern of SDN-1, we generated
transgenic animals expressing a full-length Cterminally tagged SDN-1::GFP
fusion protein. In embryos and L1 larvae, SDN-1::GFP was expressed in many
tissues, including neurons, pharynx and hypodermis
(Fig. 5A'). In later
larval stages and in adult worms, SDN-1::GFP was predominantly expressed in
the nervous system, with strong expression in the nerve ring and the VNC
motoneurons (Fig. 5B,C,E,F).
Apart from the neuronal expression, SDN-1::GFP was also found at a lower level
in the hypodermis (Fig. 5D) and
the vulval cells (data not shown). Because antibodies directed against the
conserved intracellular domain of mammalian syndecan 4 have been reported to
specifically detect C. elegans SDN-1 in the nerve ring and the vulva
(Minniti et al., 2004), the
SDN-1::GFP reporter likely reflects the endogenous SDN-1 expression
pattern.
SDN-1 functions in neurons to control cell migration and axon guidance
Based on the SDN-1::GFP expression pattern, it is conceivable that SDN-1
could affect neuronal differentiation in a cell nonautonomous manner. In
particular, SDN-1 expressed in the hypodermis might regulate the diffusion and
thus spatial distribution of secreted guidance cues. Alternatively, SDN-1
might function cell autonomously in the migrating neurons and navigating
growth cones to modulate possibly through its HS chains the
interaction of specific ligand/receptor pairs.
To distinguish between these two possibilities, we expressed a full-length
sdn-1 cDNA under the control of either the hypodermal dpy-7
promoter (Pdpy-7::sdn-1)
(Gilleard et al., 1997) or the
pan-neuronal unc-119 promoter
(Maduro et al., 2000
), and
tested the rescuing activity of the different transgenes. Interestingly,
neuron-specific expression of SDN-1, as well as expression of SDN-1 driven by
the endogenous sdn-1 promoter (Psdn-1::sdn-1) rescued the
HSN and ALM migration defects of sdn-1 null mutants
(Table 2). By contrast,
hypodermal expression of SDN-1 under control of the dpy-7 promoter
had no significant effect on ALM migration, although it did weakly reduce the
HSN migration defects (Table
2).
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For D-type motoneurons, we found that in animals lacking both HSE-5 and SDN-1 the outgrowth of commissures to the DNC was drastically reduced compared with that of either single mutant (Fig. 6A-D'). Moreover, hse-5; sdn-1 double null mutant L1 larvae showed a highly defasciculated VNC (Fig. 6C') and most of the embryonic DD commissures failed to reach the DNC (Fig. 6A,B'). We observed a similar range of defects in L4 larvae and adult animals, where most of the DD and VD commissures were misguided and did not connect to the DNC (Fig. 6D').
Similarly, sdn-1 hst-6 double-null mutants (L1 larvae and adults) showed more severe phenotypes in D-type motoneurons than did either single mutant alone, but the increase of defects was less pronounced than in hse-5; sdn-1 double-null worms (Fig. 6A, Fig. 4E). The strong enhancement of the guidance defects observed in hse-5; sdn-1 double mutants suggests that HSE-5 acts in parallel with SDN-1, i.e. that HSE-5 must modify at least one additional HSPG regulating a parallel signaling pathway. Because sdn-1 hst-6 double mutants show a detectable enhancement of guidance defects in D-type motoneurons when compared with either single mutant, SDN-1 may not be the only substrate of HST-6 in D-type motoneurons.
To expand these observations in a different cellular context, we also
examined the pathfinding of PVQ interneurons. Again, hse-5; sdn-1
double-null animals showed significantly more PVQ crossover defects than did
either single mutant (Fig. 6E).
In most hse-5; sdn-1 worms, midline crossing had already occurred in
the posterior region, leading to completely collapsed PVQ tracts (>50% of
crossover defects). In contrast to D-type motoneurons, loss of HST-6 function
did not result in a statistically significant enhancement of the
sdn-1 null phenotype. Interestingly, HST-6 is predominantly expressed
in neurons, in contrast to HSE-5, which is mainly expressed in the hypodermis
(Bülow and Hobert, 2004).
This finding, together with our observation that loss of HST-6 function does
not lead to more severe PVQ crossover defects in an sdn-1 null
background, suggests that 6O-sulfated HS, generated by HST-6, is
important for SDN-1 function in PVQ midline crossing. By contrast, in D-type
motoneurons, both hse-5; sdn-1 and sdn-1 hst-6
double-null mutants exhibited additive effects. Thus, signaling in different
cellular contexts (D-type motoneurons versus PVQ) might depend on a different
combination of HS modifications.
|
SDN-1 acts in the Slit/Robo pathway
As the above experiment showed that syndecan SDN-1 is required for midline
guidance, we speculated that SDN-1 might act as a co-receptor in one of the
known axon guidance pathways, such as UNC-6/Netrin or Slit/Robo
(Hao et al., 2001;
Ishii et al., 1992
;
Zallen et al., 1998
). The
genome encodes one Robo receptor (SAX-3) and one Slit homolog (SLT-1), which
are both required for ventral axon guidance
(Hao et al., 2001
).
Furthermore, interneurons that are usually separated in the left and right VNC
inappropriately cross the midline in mutants
(Hao et al., 2001
), a defect
similar to the phenotype that we observed in mutants.
In order to test whether SDN-1 acts in the SLT-1-dependent signaling
pathway, we used the presumptive null allele slt-1(eh15)
(Hao et al., 2001) and
compared the phenotype of slt-1 sdn-1 double-null mutants with that
of either single mutant (Fig.
6E). The midline crossing defects in slt-1 sdn-1 double
mutants were no more severe than those of either single mutant, suggesting
that SDN-1 acts in the same genetic pathway as SLT-1. Likewise, slt-1
sdn-1 double mutants did not show enhanced defects of L/R choices of
D-type motoneurons (data not shown).
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Discussion |
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Syndecan in cell migration
Loss of SDN-1 function interferes with the migration of the HSN, CAN and
ALM neurons, which, together with Q neuroblasts, are the only groups of
neurons that migrate long distances in C. elegans. Because similar
ALM migration defects have been reported for mutations in sax-3/Robo
(Zallen et al., 1999), SDN-1
might also modulate Slit/Robo signaling in cell migration, in addition to its
role in the regulation of Slit signaling in midline guidance indicated by our
data. However, lack of SDN-1 does not perturb cell migration in general; for
example, sex myoblast migration is normal in sdn-1(zh20) animals
(data not shown). Furthermore, sdn-1 null mutants exhibit no
circumferential distal tip cell (DTC) migration defects. Mutations in the gene
encoding perlecan/UNC-52, a basement membrane HSPG, enhance the DTC migration
defects of UNC-6/netrin signaling mutants an effect that can be
partially suppressed by mutations disrupting growth factorlike signaling
(Merz et al., 2003
). Whether
SDN-1 also contributes to signaling by EGL-20/WNT, UNC-129/TGF-ß or
EGL-17/FGF still needs to be determined.
Another candidate pathway that could be regulated by SDN-1 is signaling by
integrins. C. elegans ina-1 _ integrin was shown to be required in
neurons for the migration of HSN, ALM and CAN neurons
(Baum and Garriga, 1997).
Intriguingly, ina-1 mutants also show defects in coelomocyte
migration, whereas sexmyoblast migration is normal, similar to the situation
we found in sdn-1(zh20) null mutants. In addition, cell culture
studies have demonstrated a crucial role of the syndecan extracellular domain
in regulating the adhesion and invasion of tumor cells, possibly by
interacting with integrins (Beauvais et
al., 2004
; Burbach et al.,
2004
). Understanding the role of syndecan in cell migration is
particularly relevant in light of the role mammalian syndecans play during
carcinogenesis. Upregulation of human syndecan 1 in breast and pancreatic
cancer, for example, usually correlates with more invasive tumors, although,
in other types of cancer, downregulation of syndecan seems to have equally
adverse effects (Beauvais and Rapraeger,
2004
; Leivonen et al.,
2004
). In C. elegans, SDN-1 could promote cell migration
either by modulating the activity of guidance cues or, directly, by regulating
cell adhesion.
Syndecan in axon guidance
How might SDN-1 function in axon guidance? A recent study in
Drosophila has shown that loss of syndecan function affects the
extracellular distribution of the ligand Slit, which is secreted by midline
cells and might therefore interfere with signal transduction by Robo receptors
(Johnson et al., 2004). Neural
expression of Drosophila syndecan rescued the guidance defects of
syndecan mutant flies, whereas the expression of syndecan in midline cells did
not (Johnson et al.,
2004
).
Similarly, our data suggest that C. elegans SDN-1 functions in neurons to ensure the correct midline guidance of axons. Cell type-specific expression of SDN-1 in PVQ interneurons partially rescued the midline pathfinding errors of these cells, whereas expression of SDN-1 in the surrounding epidermis failed to rescue. Incomplete rescue of PVQ crossovers, also seen for SDN-1 driven by its endogenous promoter, could be explained by insufficient expression of the rescuing arrays in PVQ neurons due to the lack of an enhancer sequence in the promoters that we used.
Neuronal SDN-1 could act as a co-receptor of specific axon guidance receptors and might thereby enhance the efficacy of the signaling event (quantitative modulation), alter the specificity of the ligand/receptor interaction (qualitative modulation), or both. One good candidate for a receptor that may require SDN-1 for ligand binding is the Slit/SLT-1 receptor SAX-3. sdn-1 mutants show similar pathfinding errors as slt-1 or sax-3 mutants, and genetic epistasis analysis placed sdn-1 in the same genetic pathway as slt-1 in certain cellular contexts (PVQ and D-type motoneuron development).
Alternatively, SDN-1, being a transmembrane protein, could also act
directly as a receptor and generate an intracellular signal on its own. For
example, Xenopus syndecan 2 participates in inside-out signaling that
specifies the left-right looping of the heart and gut, which is mediated by
PKC_ phosphorylation of the syndecan cytoplasmic domain
(Kramer et al., 2002). Beyond
their function as (co-)receptors, syndecans may also be involved in the
targeting of guidance receptors to specific membrane compartments, such as
lipid rafts (Couchman,
2003
).
The C terminus of mammalian syndecans has been shown to interact with the
PDZ domain of the membrane-associated guanylate kinase CASK
(Cohen et al., 1998;
Hsueh et al., 1998
). The
C. elegans CASK homolog LIN-2 is required together with LIN-7 and
LIN-10 for the basolateral localization of the EGF receptor on vulval
precursor cells (Kaech et al.,
1998
). SDN-1 might therefore be required to anchor the
LIN-2/LIN-7/LIN-10 complex to the basolateral plasma membrane and thereby
localize the EGF/LET-23 receptor. Although SDN-1::GFP is present on the
basolateral side of the primary vulval cells (data not shown), loss of SDN-1
had no effect on EGF receptor localization. However, these observations do not
exclude a possible role for SDN-1 in the targeting of axon guidance
receptors.
|
C. elegans mutant for glypican GPN-1, the second major cell
surface HSPG, do not seem to display axon guidance or cell migration defects
(Hannes Bülow and Oliver Hobert, personal communication). In all events
that we analyzed (PVQ and DD/VD guidance, HSN migration),
gpn-1(ok377) failed to enhance the defects of sdn-1(zh20)
null animals (data not shown), indicating that HSE-5 might modify an
extracellular or as yet unknown cell surface HSPG. The UNC-6/Netrin and
VAB-1/Ephrin guidance systems act in parallel with SLT-1/Slit signaling to
define midline guidance (Zallen et al.,
1999), and are thus candidate pathways to be regulated by such
proposed epimerized sugar motifs on a HSPG core protein distinct from
SDN-1.
In PVQ interneurons, lack of the 6O-sulfotransferase HST-6 in worms devoid of SDN-1 did not cause a significant enhancement of crossover defects when compared with sdn-1 single mutants. Thus, the HS side chains on SDN-1 are likely to be important substrates of HST-6 in PVQ (Fig. 7). HST-6 is, however, also involved in SDN-1-independent signaling, in the context of D-type motoneuron guidance.
Regulation by specific sugar modifications
Our results provide further evidence for the existence of a `sugar code' on
cell-surface and extracellular HSPGs that regulates the differential responses
of axons towards the various extracellular guidance cues that they normally
encounter. For example, 6Osulfated HS side chains may act as
`molecular antennae' on SDN-1 to enhance the perception of Slit signals, as
well as a modulator for the ligand/receptor interaction, while the input from
parallel guidance systems could be regulated by extracellular HSPGs carrying
C5-epimerized HS chains, with or without 6O-sulfation
(Fig. 7). In this way, the
sensitivity of axons towards Slit signals could be dynamically regulated
through the combinatorial control of HS-modifying enzyme expression and cell
surface exposure of SDN-1. Indeed, during an early phase of mouse brain
development, the different syndecan family members, as well as the
HS-modifying enzymes, show tightly regulated spatiotemporal expression
patterns (Ford-Perriss, 2003;
Sedita et al., 2004
).
The fact that HSPGs are highly conserved from nematodes to humans supports
the idea that tissue-specific HS sugar modifications of HSPGs are a key factor
that determines the cellular specificity of the different axon guidance
systems (Hutter et al., 2000).
Rules learned in C. elegans are thus likely to also apply in mammals,
and promise to lead to a better understanding of the mechanisms that regulate
nervous system development.
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ACKNOWLEDGMENTS |
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