University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada
* Author for correspondence (e-mail: smcfarla{at}ucalgary.ca)
Accepted 18 May 2005
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SUMMARY |
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Key words: Xenopus laevis, MMP2, MMP9, Growth cone, Target recognition, Optic chiasm
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Introduction |
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A role for metalloproteinases in axon extension and guidance is also
emerging (McFarlane, 2003;
McFarlane, 2005
). Mutants of
the Drosophila ADAM10 homologue kuzbanian exhibit both axon
extension and guidance defects (Fambrough
et al., 1996
; Schimmelpfeng et
al., 2001
). Two reports have indicated that, at least in culture,
metalloproteinases are able to cleave axon guidance cues and receptors
(Galko and Tessier-Lavigne,
2000
; Hattori et al.,
2000
). The cleavage of ephrins and deleted in colorectal cancer
(DCC), the receptor for the axon guidance molecule netrin, are inhibited by
the application of broad-spectrum metalloproteinase inhibitors to embryonic
neurons growing in culture. In both cases, metalloproteinases act to terminate
axon guidance cue signalling. However, in other systems, cleavage that
activates signalling has been reported
(Diaz-Rodriguez et al., 1999
;
Mechtersheimer et al., 2001
;
Naus et al., 2004
).
We recently showed in vivo that metalloproteinases are necessary for axon
guidance in vertebrates (Webber et al.,
2002). In the developing visual system of Xenopus laevis,
retinal ganglion cell (RGC) axons make several guidance decisions en route to
their major midbrain target, the optic tectum
(Dingwell et al., 2000
). We
used an in vivo exposed brain preparation to demonstrate that
metalloproteinases are necessary for at least two of the decisions
(Webber et al., 2002
). In the
presence of a broad-spectrum hydroxamate-based metalloproteinase inhibitor,
GM6001, RGC axons failed both to make a caudal turn in the mid-diencephalon
and to recognize the optic tectum as their target.
As the hydroxamate-based inhibitors we used are known to block the activity
of both ADAMs and MMPs, it is not clear whether both metalloproteinase
families are important for RGC axon guidance. To address this issue, we used a
specific MMP pharmacological inhibitor in the Xenopus exposed brain
preparation. MMP inhibitor IV (SB-3CT) selectively targets gelatinases by
acting as a specific substrate that renders these metalloproteinases inactive
(Brown et al., 2000;
Kleifeld et al., 2001
). The
effects of blocking MMP function were distinct from those observed previously
with GM6001 in that SB-3CT had no effect on the ability of RGC axons to make
the turn in the mid-diencephalon, but caused defects in axon guidance at the
optic tectum (Webber et al.,
2002
). Furthermore, we used a second in vivo preparation to show
that both SB-3CT and GM6001 caused guidance defects at the optic chiasm. These
results implicate MMPs, for the first time, in the process of axon guidance,
and indicate that different metalloproteinases act at each axon choice
point.
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Materials and methods |
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Exposed brain and exposed optic chiasm preparations
The exposed brain preparation was performed as described previously
(Chien et al., 1993;
Webber et al., 2002
). Briefly,
embryos were anesthetized in modified Barth's solution (MBS) supplemented with
0.4 mg/ml tricaine (ethyl 3-aminobenzoate methane-sulfonic acid; Sigma,
Oakville, Ontario, Canada), 50 mg/ml gentamicin sulfate (Sigma) and 10 mg/ml
Phenol Red (Sigma). One set of experiments involved removing the skin and dura
covering the left brain at stage 33/34 to expose the entire anterior brain on
one side. In a second series of experiments, the optic chiasm was exposed at
stage 30-31 by removing the cement gland and mesenchyme underlying the ventral
forebrain. After surgery, the embryos were left to develop in either
experimental or control MBS solutions for another 18-24 hours until they
reached stage 40. The experimental solutions were MBS with 5-75 µM
MMP2/MMP9 Inhibitor IV (SB-3CT; Chemicon, Temecula, CA), 100-400 µM of a
specific peptide gelatinase inhibitor, cyclic CTTHWGFTLC (cyclic CTT) (Biomol,
Plymouth Meeting, PA) or 5-10 µM GM6001 (Calbiochem, EMD Biosciences,
Darmstadt, Germany). The control solution consisted of MBS (pH 7.4) with
0.05-0.4% dimethyl sulfoxide (DMSO), the solvent in which the inhibitor
solutions were made. Compounds related to GM6001,
N-t-butoxycaronyl-L-leucyl-L-tryptophan methylamide (Calbiochem, EMD
Biosciences) and CTT, STTHWGFTLC (STT; Biomol) but with no effect on
proteolytic activity were used as negative controls.
Visualization of the optic projection
The optic projection was visualized by anterogradely labelling RGC axons
using horseradish peroxidase (HRP, type VI; Sigma) as described previously
(Cornel and Holt, 1992).
Briefly, the lens of the right eye was surgically removed and HRP dissolved in
1% lysolecithin was placed in the eye cavity. Embryos were fixed overnight in
4% paraformaldehyde in 0.1 M sodium phosphate buffer (pH 7.4). Dissected
brains were washed in phosphate-buffered saline (PBS), reacted with
diaminobenzidine (Sigma), dehydrated through a graded series of alcohols and
cleared in 2:1 benzyl benzoate:benzyl alcohol. The outlines of brains and
optic projections were drawn using a camera lucida attachment on a Zeiss
(Thornwood, NY) microscope. All digital images in this study were taken with a
Spot II camera and Spot Advanced software (Diagnostics Instruments), and
processed for brightness and contrast by using Adobe Photoshop (7.0) software.
We used three reliable morphological landmarks to identify the anterior border
of the tectum: the point where the second ventricle enlarges into the third,
the posterior border of the neuropil of the tract of the posterior commissure
and the position of the dorsolateral isthmus between the diencephalon and
midbrain.
Quantification of optic projection length and turning angle
The effects of the MMP inhibitor were quantified by measuring the length
and turning angle of optic projections in control and treated brains. Camera
lucida representations were scanned with an Astra 1200s flatbed scanner (Umax,
Freemont, CA) to provide digital images. Analysis was performed using the
public domain NIH Image program. Brains were normalized by using macro
programs described previously (Chien et
al., 1993), by rotating and scaling them to a line drawn between
the anterior optic chiasm and the midbrain-hindbrain isthmus. This line was
matched to a standard reference line, artificially defined as 1 brain
reference unit (b.r.u.); 1 b.r.u. is
620 µm in an unfixed brain
(Chien et al., 1993
). The optic
tract length was measured from the optic chiasm to the end of the optic
projection, operationally defined as containing at least 10 axons. The angle
through which the optic projection makes a turn in the mid-diencephalon was
also measured (see Webber et al.,
2002
) (see Fig.
2A). A line (2) was drawn at a 60° angle to the reference line
(1) between the optic chiasm and midbrain-hindbrain isthmus, bisecting the
optic tract at the level of the turn made in the mid-diencephalon. The angle
was measured between this line (2) and a line (3) drawn through the middle of
the optic tract in its initial projection past the turn. Samples were compared
statistically by using an unpaired ANOVA, followed by a Student-Newmann-Keuls
multiple comparison post hoc test (Instat 2.0; GraphPad Software, San Diego,
CA).
Immunocytochemistry
Embryos were exposed at stage 31 to either control media or media
containing 25 µM SB-3CT. At stage 37/38, embryos were fixed overnight in 4%
paraformaldehyde and 12 µm frozen transverse sections were cut through the
brain and eyes by using a cryostat (Microm, San Marcos, CA). Briefly, sections
were rinsed several times in PBT [PBS, 0.5% Triton (BDH), 0.1% bovine serum
albumin (Sigma)], blocked in PBT+5% goat serum (Invitrogen Canada, Burlington,
ON) and incubated overnight at 4°C in the primary antibody. Goat
anti-mouse Rhodamine Red X (RRX) secondary antibodies (Jackson ImmunoResearch
Laboratories, West Grove, PA; 1:500) were applied the next day for 1 hour at
room temperature. After rinsing in PBT, samples were mounted in glycerol with
an anti-bleaching agent, polyvinyl alcohol (Sigma). Primary antibodies were as
follows: mouse 3CB2 [Developmental Studies Hybridoma Bank (DSHB), University
of Iowa, IA; 1:10], mouse Zn-12 (DSHB; 1:40), mouse islet-1 (DSHB; 1:100) and
rabbit GABA (Sigma, 1:3000).
In situ hybridization
Templates for riboprobe synthesis included a 1.5 kb fragment of the
Xenopus MMP2 cDNA cloned into pBSK- (kindly provided by J.-C. Jung)
(Jung et al., 2002), and the
full coding region of Xslit (kindly provided by J. Wu)
(Chen et al., 2000
). Antisense
digoxigenin-labelled riboprobe was transcribed with T7 RNA polymerase
(Promega, Madison, WI). In situ hybridization was performed as described
previously (Sive, 2000). Briefly, embryos were fixed in MEMFA (0.1 M MOPS, pH
7.4, 2 mM EGTA, 1 mM MgSO4, 3.7% formaldehyde) for 1 hour and then
dehydrated in ethanol and stored at 20°C until further use.
Hybridization was performed overnight at 60°C. The probe was detected
using alkaline phosphatase linked anti-digoxigenin antibodies and BM-Purple
substrate (Roche, Mississauga, ON). Embryos were postfixed in Bouin's fixative
(1% picric acid, 5% acetic acid, 9.25% formaldehyde), washed several times in
buffered ethanol (70% ethanol, 30% PBS), rehydrated in PBS and embedded in
gelatin-albumin (Sigma) blocks for vibratome sectioning. Sections were cut at
50 µm on a Vibratome series 1000 (Ted Pella, Redding, CA), and then
dehydrated through a series of alcohols. Finally, sections were cleared in
xylene and mounted under glass coverslips with Permount (Fisher Scientific
Company, Pittsburgh, PA).
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Results |
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In control embryos, RGC axons extended dorsally, and then made a caudal
turn in the mid-diencephalon before continuing on to their dorsal midbrain
target, the optic tectum (Fig.
1A). In the presence of 10-25 µM of SB-3CT, the majority of RGC
axons extended normally and made the diencephalic turn
(Fig. 1B,C). However, upon
reaching the optic tectum, many axons failed to recognize the tectum as their
target and instead turned and grew dorsally. This phenotype was not observed
in any of the control embryos (n=36), but increasing the SB-3CT
concentration resulted in greater numbers of embryos with mistargeted axons;
22% (n=18) for 10 µM, 51% (n=43) for 25 µM, and 70%
(n=27) for 50 µM. At higher concentrations (50-75 µM), the
optic projections were often shorter than controls
(Fig. 1D). Only one embryo had
a shortened optic projection in control (n=41) and 10 µM
SB-3CT-treated brains (n=18), whereas 23% (n=47) of 25
µM, 45% (n=33) of 50 µM and 60% (n=15) of 75 µM
SB-3CT-treated brains exhibited RGC axon extension defects. Importantly, an
unrelated cyclic peptide MMP (gelatinase) inhibitor, CTT (400 µM), produced
a similar mistargeting phenotype (53%, n=15; compare
Fig. 1B with 1F)
(Koivunen et al., 1999).
Similar concentrations were required to block migration of tumour and
endothelial cells in vitro (Koivunen et
al., 1999
). By contrast, the optic projection formed normally when
the brains were exposed to a closely related inactive peptide, STT (9/11) or
to a control solution (8/8) (Fig.
1E). The fact, that two different inhibitors produce similar
target recognition defects argues for the specificity of the effect for MMP
inhibition.
To quantitate the effects of SB-3CT, two parameters were measured; the
length of the optic projection and the angle through which RGC axons make a
turn in the mid-diencephalon. Previously, we have found that GM6001 altered
the turning angle of RGC axons at the mid-diencephalic turn, implicating
metalloproteinases in this guidance decision
(Webber et al., 2002). In
GM6001-treated brains, axons failed to make the turn, and, as such, grew
towards the pineal gland and never reached the anterior border of the optic
tectum. By contrast, axons in SB-3CT-treated brains made the turn in the
mid-diencephalon, ultimately reached the tectal border, and then failed to
recognize their target. In agreement, similar turning angles were observed for
control and SB-3CT treated embryos (Fig.
2A), which argues that an SB-3CT sensitive MMP is not important at
the mid-diencephalic guidance choice point. Interestingly, the optic
projection length was relatively unaffected by the low inhibitor doses (10 and
25 µM) that caused guidance defects, but was inhibited significantly at
higher concentrations (Fig.
2B).
|
|
The two metalloproteinase inhibitors had similar effects on axon behaviour in the ventral forebrain (Fig. 3). In control embryos (62/70), or embryos exposed to a chemical related to GM6001 but unable to inactivate metalloproteinases (GM6001 negative control) (55/62), axons extended normally into the contralateral diencephalon (Fig. 3A,B). By contrast, few embryos had normal optic projections upon treatment with the metalloproteinase inhibitors. With 25 µM SB-3CT, only 2/22 embryos had optic projections that reached the dorsal diencephalon. The remaining SB-3CT-treated embryos had shorter optic projections, and the vast majority of these projections failed to enter the contralateral diencephalon altogether (14/20) (Fig. 3C). Interestingly, these severe axon extension defects were observed at a concentration of SB-3CT that had little effect on axon extension in the exposed brain preparation (see Fig. 1B, Fig. 2B). Similar defects in axon extension were observed with GM6001. With both 5 and 10 µM GM6001, the predominant defect was for axons to fail to project into the contralateral diencephalon (9/33 of embryos with 5 µM GM6001 and 28/35 of embryos with 10 µM GM6001) (Fig. 3D). Significantly, 5 µM GM6001 had no effect on its own on basal RGC neurite extension in vitro (data not shown), which argues that in vivo the metalloproteinase inhibitors are affecting axon outgrowth regulated by extrinsic cues.
|
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SB-3CT causes no obvious defects in the optic pathway from the retina to the ventral diencephalon
SB-3CT could cause defects in the behaviour of RGC axons in the ventral
diencephalon via non-specific disruption of the optic pathway. To ensure that
the retinas, optic nerve and ventral diencephalon developed normally in
SB-3CT-treated brains we examined the expression of a number of markers in
embryos treated in the exposed chiasm preparation with either a control
solution or 25 µM SB-3CT. We found that:
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Discussion |
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Certainly, a number of MMPs, including MMP2, are expressed in the growth
cones of vertebrate neurites extending in vitro
(Chambaut-Guerin et al., 2000;
Hayashita-Kinoh et al., 2001
;
Nordstrom et al., 1995
;
Zuo et al., 1998
). There is a
suggestion from the literature that MMPs act to degrade the ECM to ease the
movement of an axon forwards, as growth factor-treated pheochromocytoma cells
that express antisense mRNA for stromelysin-1/MMP3 have problems extending
through a basal lamina culture matrix
(Nordstrom et al., 1995
). Our
data indicate that the role of MMPs in axon guidance is not simply to digest a
path through the ECM via which RGC axons can extend, in that axon guidance
defects were observed at SB-3CT doses with little or no effect on axon
extension. Thus, it is likely that MMPs directly cleave RGC axon guidance cues
or the growth cone receptors, as is the case for ADAMs
(Galko and Tessier-Lavigne,
2000
; Hattori et al.,
2000
). A comparison of our SB-3CT and GM6001 data supports the
idea that both ADAMs and MMPs are required for the proper guidance of RGC
axons. For example, at the optic chiasm GM6001 and the MMP inhibitor showed
overlapping, but distinct axon guidance phenotypes: defasciculation was
observed only with GM6001 treatment.
It is unclear whether metalloproteinases function directly in RGC growth
cones, or in the substrate through which they extend. The growth cones of a
number of different neurons express MMPs
(Chambaut-Guerin et al., 2000;
Hayashita-Kinoh et al., 2001
;
Nordstrom et al., 1995
;
Zuo et al., 1998
). However,
MMP2 is expressed by tissues surrounding the optic pathway, and not by RGCs.
Thus, MMP2 may be secreted and diffuse into the optic pathway to influence the
behaviour of RGC axons. The fact that two chemically distinct
MMP2/MMP9-specific inhibitors produced similar mistargeting phenotypes lends
support for such a role for MMP2. A caveat is that in the exposed brain and
chiasm experiments, a significant amount of MMP2-expressing tissue would have
been removed surgically. It is likely that enough MMP2 expressing tissue
remained in both experimental preparations or that MMP2 was secreted and
diffused to the optic pathway prior to surgery, and thus was present in the
exposed preparations. The possibility remains, however, that another MMP(s) is
inhibited by SB-3CT and is the one that is important in RGC axon guidance. For
example, MMP11 and MMP13 are expressed in the Xenopus eye at stages
when RGC axons extend through the brain
(Damjanovski et al., 2000
).
The inhibitor was designed to specifically target gelatinases, and inhibits
MMP2 and MMP9 at 1000-fold lower concentrations than other MMPs
(Brown et al., 2000
). Although,
in general, higher concentrations are required in vivo than in vitro, it is
possible that the SB-3CT concentrations used in our experiments blocked other
MMPs not officially classified as gelatinases, but that can cleave this
substrate (Brown et al., 2000
;
Isaksen and Fagerhol,
2001
).
Our data argue that an MMP(s) functions in some but not all guidance
decisions within the diencephalon. However, the GM6001 results indicate that
metalloproteinase function is required at all the decision points we have
examined (Webber et al.,
2003). Thus, guidance in the mid-diencephalon and fasciculation of
axons at the optic chiasm, which were specifically affected by GM6001,
probably requires either an ADAM or a non-gelatin processing MMP. Thus,
different metalloproteinases may function in the guidance of RGC axons in
distinct brain regions. A second possibility is that the guidance cues
targeted by MMPs vary along the optic pathway. Certainly, guidance cues show
distinct expression patterns in the developing Xenopus visual system
(Campbell et al., 2001
;
de la Torre et al., 1997
). It
is likely that some combination of the two explanations is at work. These same
arguments can be used to explain why axon extension was differentially
affected at the optic chiasm and in the diencephalon by the same SB-3CT
concentration.
What guidance cues could be affected by MMP inhibition? Aside from the
optic chiasm, little is known about the guidance pathways involved at each of
the decision points within the diencephalon
(Dingwell et al., 2000;
Mason and Erskine, 2000
;
Oster et al., 2004
;
Williams et al., 2004
).
Intriguingly, metalloproteinases have been implicated in the processing of
either the cue or the receptor of all those that are known. Possible
metalloproteinase targets at the optic chiasm are Slits or their receptors,
Robos. This signalling system is required for proper axon guidance at the
optic chiasm both in mouse and zebrafish
(Fricke et al., 2001
;
Plump et al., 2002
). Mice that
are double mutant for slit1 and slit2 have significant
numbers of axons that project into the contralateral optic nerve
(Plump et al., 2002
), similar
to what we observed with metalloproteinase inhibition. Whether MMPs directly
cleave either Slits or Robos is unknown. However, kuzbanian, the
Drosophila homologue of ADAM10, interacts genetically with
slit and robo
(Schimmelpfeng et al., 2001
).
It has been proposed that Slits act to channel RGC axons at the optic chiasm
(Fricke et al., 2001
;
Plump et al., 2002
).
Potentially, preventing normal cleavage of Slits or Robos interferes with this
mechanism and results in axons that either aberrantly enter the contralateral
optic nerve or defasciculate.
Metalloproteinase-sensitive targets at the optic tectum could include the
FGF and netrin guidance pathways. Interestingly, we have found that both
inhibiting and promoting FGF signalling produces a RGC axon target recognition
defect similar to that observed with the MMP inhibitor
(McFarlane et al., 1996;
McFarlane et al., 1995
). MMP2
can release the soluble ectodomain of FGFR1
(Levi et al., 1996
). We
observed that GM6001 inhibited FGF2 stimulated RGC neurite extension in vitro
(data not shown), which suggests a scenario where an MMP-cleaved FGFR
ectodomain would function to promote FGF2 actions on RGC axons. In general,
however, soluble FGFR ectodomains are thought to act as inhibitors of FGF
signalling (Celli et al., 1998
;
Guillonneau et al., 1998
;
Mandler and Neubuser, 2004
).
Possibly, then, the GM6001/SB-3CT mechanism involves blocked cleavage of
heparan sulfate proteoglycans (HSPGs) by growth cone metalloproteinases.
Metalloproteinases can cleave HSPGs, and soluble heparan sulfate promotes FGF
signalling (Endo et al., 2003
;
Winkler et al., 2002
). As the
normal presentation of FGF cues involved in RGC axon target recognition also
appears to depend on HSPGs (McFarlane et
al., 1996
; McFarlane et al.,
1995
; Walz et al.,
1997
), interference with HSPG processing either in RGC axons or
brain neuroepithelial cells could explain the axon target recognition defects
we observed with metalloproteinase inhibition. An alternate explanation
involves the netrin 1 receptor, DCC, which is also cleaved by
metalloproteinases (Galko and
Tessier-Lavigne, 2000
). Because in this in vitro study
broad-spectrum metalloproteinase inhibitors were used, it was not determined
whether an ADAM or MMP was important for cleavage. In Xenopus, netrin
1 is expressed deep to the termination field of axons within the optic tectum,
and in vitro netrin repulses RGC growth cones at a stage when they innervate
the tectum (Shewan et al.,
2002
). Thus, an inhibitor of DCC cleavage might sensitize RGC
axons to netrin and cause them to avoid the tectum altogether, the phenotype
we observed with the MMP inhibitor.
Our data argue that an MMP, possibly MMP2, functions in the guidance of RGC axons at several different decision points within the brain. An alternate metalloproteinase, however, functions in the guidance of these axons at the mid-diencephalon. Future experiments will need to identify the specific metalloproteinases important in guidance of RGC axons at each decision point, and address their potential targets.
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ACKNOWLEDGMENTS |
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