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First published online 15 August 2007
doi: 10.1242/dev.007112
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Research Report |
University of Pennsylvania School of Medicine, Department of Cell and Developmental Biology, Philadelphia, PA 19104-6058, USA.
* Author for correspondence (e-mail: granatom{at}mail.med.upenn.edu)
Accepted 10 July 2007
SUMMARY
One of the earliest guidance decisions for spinal cord motoneurons occurs when pools of motoneurons orient their growth cones towards a common, segmental exit point. In contrast to later events, remarkably little is known about the molecular mechanisms underlying intraspinal motor axon guidance. In zebrafish sidetracked (set) mutants, motor axons exit from the spinal cord at ectopic positions. By single-cell labeling and time-lapse analysis we show that motoneurons with cell bodies adjacent to the segmental exit point properly exit from the spinal cord, whereas those farther away display pathfinding errors. Misguided growth cones either orient away from the endogenous exit point, extend towards the endogenous exit point but bypass it or exit at non-segmental, ectopic locations. Furthermore, we show that sidetracked acts cell autonomously in motoneurons. Positional cloning reveals that sidetracked encodes Plexin A3, a semaphorin guidance receptor for repulsive guidance. Finally, we show that sidetracked (plexin A3) plays an additional role in motor axonal morphogenesis. Together, our data genetically identify the first guidance receptor required for intraspinal migration of pioneering motor axons and implicate the well-described semaphorin/plexin signaling pathway in this poorly understood process. We propose that axonal repulsion via Plexin A3 is a major driving force for intraspinal motor growth cone guidance.
Key words: Zebrafish, Growth cone, Axon, Guidance, Myotome, Plexin A3, Sidetracked, Spinal motoneuron
INTRODUCTION
In recent years, many of the basic principles of axonal guidance have been
defined at the molecular and cellular levels (reviewed in
Dickson, 2002
). Work in
vertebrates and in invertebrates has shown that a small group of conserved
guidance molecules, including ephrins, netrins, semaphorins and slits, via
their cognate receptors, steer axons towards their synaptic targets. It is
also clear now that axonal trajectories are broken down into segments, and
that individual guidance decisions along these segments are controlled
independently (i.e. using divergent guidance cue/receptor pairs). Although
this enables a relatively small number of guidance molecules to generate the
intrinsic patterns of neural connectivity, one of the remaining challenges is
to `reconstruct' for each neural cell type all the cue/receptor pairs that
control each decision along its entire axonal trajectory.
For motor axon trajectories, one of the first guidance decisions is their
longitudinal migration towards a segmental spinal cord exit point. Although
the spinal cord is externally unsegmented, motor axons exit and sensory
afferents enter through distinct, segmentally organized zones along the
anteroposterior axis - the motor exit points (MEPs) and the dorsal root entry
zone (DREZ), respectively. During development, growth cones from motoneurons
located within a spinal segment navigate longitudinally towards a shared
segmental exit point. In rodents and birds, these segmental exit points are
marked by Krox20 (Egr2)-positive cells - the boundary cap cells
(Golding and Cohen, 1997;
Niederlander and Lumsden,
1996). Elegant ablation studies have shown that boundary cap cells
are important to confine motoneuron somata to the spinal cord, but that they
appear to be dispensable for guiding motor growth cones
(Vermeren et al., 2003). In
contrast to later steps of motor axon guidance, the cellular and molecular
mechanisms by which motor axons navigate towards the segmental exit point,
recognize these zones and subsequently turn ventrally to exit, are poorly
understood.
In the zebrafish, three distinct and identifiable motor axons pioneer into
the periphery through a common, mid-segmental exit point
(Fig. 1A)
(Eisen et al., 1986). Because
Krox20-positive boundary cap cells have not been identified in zebrafish,
caudal primary (CaP) motoneurons located just dorsal of the exit points can be
used as a landmark for the exit zone (Fig.
1A). CaP growth cones do not migrate longitudinally, but extend
ventrally into the periphery. By contrast, the growth cones of middle primary
(MiP) and rostral primary (RoP), the somata of which are located further
rostrally, navigate within the spinal cord towards the segmental exit point
(Fig. 1A). Once they exit the
spinal cord, CaP, MiP and RoP growth cones pioneer a common path towards a
somitic choice point, at which they diverge onto cell-type-specific
trajectories (Fig. 1A)
(Eisen et al., 1986;
Myers et al., 1986). Because
each of these primary motoneuron subtypes can be identified and visualized by
their stereotyped axonal trajectories and cell body position, they present an
excellent system in which to study motor axon guidance, including their
intraspinal navigation, at single-cell resolution
(Beattie et al., 2002).
In this manuscript, we identify the guidance receptor Plexin A3 to play a
major role in intraspinal motor axon guidance (see below). Plexins are
transmembrane receptors containing a Semaphorin (Sema) domain followed by a
cysteine-rich Met-related domain and a unique and conserved Sex-Plexin domain
(SP) in the cytoplasmatic region
(Tamagnone et al., 1999).
Based on sequence similarity, vertebrate plexins are divided into four
subfamilies (A-D), and, in mammals, plexin A3 has been shown to mediate axonal
repulsion by Sema3A and Sema3F in sympathetic and sensory neurons
(Yaron et al., 2005;
Cheng et al., 2001). Most of
the secreted class 3 semaphorins, including Sema3A and Sema3F, do not bind
plexins directly, but signal via a receptor complex composed of one of the
four A plexins and the obligate co-receptors neuropilin 1 or neuropilin 2
(Chen et al., 2000;
Giger et al., 2000). While the
neuropilins bind the ligand, the plexins transduce the signal through their
cytoplasmic SP domain. Although members of the plexin A subfamily have been
shown to control the development of several sensory and CNS trajectories,
little is known about the specific role that they play during vertebrate motor
axon guidance.
|
). Here, we
show that the sidetracked gene plays a crucial role early during
guidance, when pioneering motor growth cones navigate towards and then through
the segmental exit point. We positionally cloned the sidetracked gene
and showed that it encodes Plexin A3. Using single-cell labeling, time-lapse
microscopy and chimera analysis we characterized this previously unknown
function of Plexin A3. During intraspinal migration of motor growth cones,
Plexin A3 acts cell autonomously to direct subsets of growth cones, those
further away, towards the segmental exit point. We propose that this is due to
repulsive Plexin A3 signaling, possibly triggered by semaphorins secreted from
the posterior somite. Thus, our results provide the first molecular genetic
insights into the earliest pathfinding events of spinal motor axons, when they
orient and path-find inside the spinal cord towards the exit point. MATERIALS AND METHODS
Fish maintenance and breeding
All experiments, except where indicated, were performed with the
sidetrackedp55emcf allele
(Birely et al., 2005). The
Tg(Hb9:GFP) transgenic line
(Flanagan-Steet et al., 2005)
primarily labels motoneurons, but also labels ventral interneurons, presumably
ventral longitudinal descending spinal interneurons (VeLDs).
Antibody stainings and in situ hybridization
Antibody stainings were performed as previously described
(Zeller et al., 2002). The
following primary antibodies were used: znp-1 [1:200;
(Trevarrow et al., 1990);
Antibody Facility, University of Oregon]; and SV2 (1:50, Developmental Studies
Hybridoma Bank, University of Iowa). Antibodies were visualized with
corresponding Alexa-Fluor-488, -546 or -594 conjugated secondary antibodies
(1:500; Molecular Probes, Eugene, OR). Embryos were imaged using confocal
microscopy. Colorimetric in situ hybridizations were performed according to
Odenthal and Nusslein-Volhard (Odenthal
and Nusslein-Volhard, 1998). Images were processed using Adobe
Photoshop and Adobe Illustrator.
Chimeric embryos
Chimeric embryos were generated and analyzed as previously reported
(Zeller and Granato, 1999).
Donor cells were from Tg(Hb9:GFP) transgenic embryos.
Time-lapse microscopy
Wild-type and mutant embryos bearing the Tg(Hb9:GFP) transgene
were anesthetized in 0.02% tricaine and embedded in 1.5% low-melting-point
agarose. Time-lapse analysis was carried out on a confocal microscope. At
3-minute intervals, z-stacks of 
15 µm were captured and then
flattened by maximum projection.
Labeling and scoring of labeled motoneurons
Embryos were injected with Hb9:GFP plasmid at the one-cell stage
and allowed to develop to 24 hours post fertilization (hpf). Fixed embryos
were stained with anti-GFP and SV2 antibodies, mounted and confocal images
taken. For scoring, we measured the distance between outlying segmental exit
points (a), and between the soma and the endogenous exit point (b). We then
calculated the ratio (a:b) and found that, for wild-type MiP (0.19-0.45) and
RoP (0.22-0.57), the ratio is between 0.19 and 0.57, whereas, for CaP:VaP,
this ratio is always less than 0.19. We then applied this to
sidetracked mutants and considered all soma with a ratio between 0.19
and 0.57 as presumptive MiP/RoP neurons.
|
RESULTS AND DISCUSSION
sidetracked guides motor growth cones towards the segmental exit points
We had previously shown that, in sidetracked mutants, motor axons
displayed two prominent phenotypes: branching at various points along the axon
and exiting from the spinal cord at ectopic locations
(Fig. 1B,C)
(Birely et al., 2005). To
identify which of the three subpopulations (CaP, MiP, RoP) exit ectopically,
we labeled individual motoneurons by injecting the motoneuronal
Hb9:GFP construct into one-cell-stage embryos
(Flanagan-Steet et al., 2005).
This results in embryos with a number of stochastically labeled motoneurons.
Analysis based on cell body position and axonal trajectory of wild-type
siblings at 24 hours post fertilization (hpf) revealed the stereotypic somata
position and axonal trajectories for RoP, MiP and CaP, demonstrating that all
three primary motoneurons are labeled by this method
(Fig. 1D-F; see Materials and
methods for scoring of individual motoneurons). In addition, this also labeled
a fourth, variable primary motoneuron, VaP, which is present in less than 50%
of the hemisegments, and which is also located dorsal to the exit zone,
adjacent to CaP (Eisen et al.,
1990).
By contrast, analysis of sidetracked mutants revealed that motoneuron somata located immediately above the endogenous exit point (i.e. presumptive CaP/VaP neurons) were unaffected (14/15; Fig. 1G), whereas approximately 50% (17/32) of motoneurons with cell bodies located rostrally to the exit point (i.e. presumptive MiPs and RoPs) displayed dramatic pathfinding defects. In mutants, presumptive RoP/MiP axons projected towards the exit point but bypassed it (6/32, Fig. 1H,I), or, instead of projecting caudally towards the exit point, projected rostrally (4/32, Fig. 1J), or exited ectopically at the position of their cell body (7/32, Fig. 1K,L). Thus, single-cell labeling demonstrates that the sidetracked phenotype is not simply caused by axonal overgrowth, but rather that sidetracked plays a pivotal role in intraspinal guidance.
We next used time-lapse microscopy to examine the behavior of sidetracked growth cones in intact, live embryos. In Tg(Hb9:GFP); sidetracked siblings, motor axons exited at segmental exit points and navigated into the periphery (Fig. 2A and see Movie 1 in the supplementary material). In Tg(Hb9:GFP); sidetracked mutants CaP and VaP axons navigate like their wild-type counterparts through segmental exit points, whereas presumptive RoP/MiP axons exit at ectopic positions, taking novel paths into the periphery (Fig. 2B and see Movie 2 in the supplementary material). By contrast, presumptive VeLD interneurons, axons of which extend caudally, navigate properly in sidetracked mutants (Fig. 1A,B, arrowheads), suggesting that intraspinal guidance in general is unaffected.
|
)]. Moreover, cell transplantations have shown that, when
placed in ectopic locations, motoneurons either develop axonal trajectories
appropriate for their original soma positions or appropriate for their new
soma position, but never exit the spinal cord at ectopic positions
(Eisen, 1991). Thus, we
conclude that sidetracked primarily guides growth cones of the
distantly located RoP and MiP motoneurons towards the segmental exit
point.
Finally, we found that sidetracked is also crucial for axonal
morphogenesis once motor growth cones navigate the periphery. In contrast to
Hb9:GFP-labeled wild-type axons, sidetracked motor axons already
displayed excessive branching along the entire shaft at 24 hpf. This is
unlikely to be a mere consequence of inappropriate axonal pathfinding, because
sidetracked motor axons that exited through the endogenous exit point
also displayed this phenotype (Fig.
2C,D). In sidetracked mutants, exuberant branching became
even more pronounced at 48 hpf (Fig.
2E,F). In wild-type embryos, such extensive side branches have
only developed by around 72 hpf, and invade the myotome to form distributed
and myoseptal neuromuscular synapses
(Downes and Granato, 2004;
Liu and Westerfield, 1990),
suggesting that sidetracked functions to restrict motor axons from
extending into non-synaptic muscle territories precociously. Thus,
sidetracked motor axons exit at ectopic spinal cord locations and
also form excessive branches that invade inappropriate territories, consistent
with the idea that both phenotypes are caused by defective axonal
repulsion.
sidetracked encodes the zebrafish Plexin A3 guidance receptor
We first used bulk segregant analysis to locate the sidetracked
mutation on chromosome 8 (Fig.
3A). We then refined the map position by meiotic recombination
mapping, defining a crucial interval between marker fb82f05.x1 (1/420
recombinants) and marker Z43564b (2/598 recombinants). On the ENSEMBL genome
assembly, these two markers delineate a 480 kb interval, in which many
predicted and three known protein coding genes are located: sodium and
chloride dependent creatine transporter 1 (ENSDARG00000043646),
calcium/calmodulin-dependent protein kinase type 1b (ENSDARG00000043648) and
plexin A3 (ENSDARG00000007172)
(Fig. 3A). The conceptually
translated protein (XM_690717) is 61% identical to zebrafish Plexin A4
(NP_001004495) but 73% identical to human and mouse Plexin A3, suggesting that
XM_690717 encodes zebrafish Plexin A3. Sequencing of the plexin A3
coding region from sidetracked mutants revealed a single base-pair
change (T2312A), resulting in a nonsense mutation, truncating the protein at
position 662 in the second PSI (Plexin-Semaphorin-Integrin) domain
(Fig. 3B,C). Because this
truncates the protein before the transmembrane domain and the signal
transducing Sex-Plexin domain, the sidetrackedp13umal
allele probably represents a null allele. Although it is possible that the
truncated protein is expressed, it is unlikely that it retains biological
activity because it lacks both the transmembrane and the signal transducing
domains. Thus, given the absence of a second plexin A3 in the
zebrafish genome, sidetracked mutants probably lack all Plexin
A3-mediated semaphorin signaling.
|
). To determine whether sidetracked indeed functions
in these two motoneurons, we generated chimeric embryos in which labeled
wild-type blastula cells were transplanted into age-matched
sidetracked hosts. Analysis of 26 hpf chimeric embryos revealed that
MiP and RoP motoneurons derived from wild-type donors developed wild-type-like
axonal trajectories in sidetracked mutants (n=6/6 RoPs, 6/6
MiPs, Fig. 4A). Conversely,
mutant-derived motoneurons developed sidetracked-like axonal
trajectories when transplanted into wild-type hosts (n=4/6 RoPs; 4/5
MiPs; Fig. 4B). Thus, Plexin A3
acts cell autonomously in MiP and RoP, suggesting a role as a receptor that is
crucial for intraspinal guidance.
How does Plexin A3 control intraspinal motor axon guidance? In most
circumstances in which it has been examined, type A plexins transduce axonal
repulsion (reviewed in Negishi et al.,
2005; Tamagnone et al.,
1999). One attractive model is that Plexin A3-sensitive RoP and
MiP growth cones avoid a repellent that diffuses anteriorly and posteriorly
from the posterior part of each somite
(Fig. 4E,F). Such a simple
model would explain why wild-type RoP and MiP growth cones migrate caudally to
a mid-segmental point, where repulsion would be minimal. It would also account
for the various pathfinding defects observed in sidetracked mutants:
RoP and MiP, now insensitive to the repellent, bypass the endogenous exit
point, or turn rostrally towards the next anterior exit point
(Fig. 1H,J), or just exit the
spinal cord below their soma (Fig.
1K,L).
We next examined the distribution of known plexin ligands at the posterior
somite compartment. Plexin A family members function in a complex with
neuropilins as receptors for semaphorins, in particular for Sema3 family
members (reviewed in Negishi et al.,
2005). In the zebrafish, a number of Sema3 family members have
been identified, including Sema3Aa (Yee et
al., 1999), Sema3Ab (Roos et
al., 1999), Sema3C (Yu and
Moens, 2005), Sema3D (Halloran
et al., 1999), Sema3Fa, Sema3Fb, Sema3Ga, Sema3Gb
(Yu and Moens, 2005) and
Sema3H (Stevens and Halloran,
2005). Of these, Sema3Aa has been reported to be expressed in the
posterior region of each somite, and knockdown of sema3Aa and
nrp1a expressed in motoneurons affects axon guidance in the periphery
(Feldner et al., 2005;
Sato-Maeda et al., 2006). We
therefore examined two other semaphorin ligands, Sema3Fa and Sema3Ab. In
sensory and sympathetic neurons, the Plexin A3-Neuropilin 2 complex
preferentially transduces the activities of Sema3F semaphorins
(Yaron et al., 2005). Whereas
sema3Fa is expressed diffusely in ventral somites
(Fig. 4C), Sema3Ab is localized
in a discrete band in the posterior part of each somite
(Fig. 4D)
(Roos et al., 1999), more
consistent with our model. However, systematic studies to examine the
expression patterns of all semaphorin genes, as well as additional functional
studies, will be required to identify the precise mechanisms by which Plexin
A3 mediates intraspinal axonal guidance.
Independent of the model, our studies, as well as those by Tanaka et al. in
this issue (Tanaka et al.,
2007), provide the first genetic demonstration that Plexin A3
signaling plays a crucial role during intraspinal motor axon guidance.
Although previous studies have demonstrated a role for class 3 semaphorins and
neuropilins in later stages of motor axon guidance [i.e. in the periphery
(Huber et al., 2003)], our
results clearly implicate a plexin signaling pathway in the very early steps,
when growth cones orient towards the segmental exit point. The finding that
sidetracked encodes Plexin A3 provides two novel insights. First, our
results show that motor axons can exit the spinal cord at seemingly random
positions. Previous studies had suggested that sites of axonal entry or exit
from the spinal cord are restricted and prefigured by the presence of
specialized neural crest derivatives - the boundary cap cells
(Niederlander and Lumsden,
1996). Our results suggest that the neural tube is competent to
form exit points along its entire length, but that the precise locations of
segmental exit points are determined by the growth cone.
Second, intraspinal guidance towards spinal exit points is governed, at
least in part, by repulsive guidance. In the chick, elegant rotation
experiments have shown that inverting rhombomeres in their anteroposterior
orientation does not alter the growth of motor axons towards their
anterior-lying exit points, which suggested that exit points represent a
chemoattractive, intermediate target guiding motor axons
(Guthrie and Lumsden, 1992).
Our results clearly demonstrate that intraspinal guidance requires Plexin A3
signaling, which propagates the repulsive activities of semaphorins. Our model
is consistent with recent results obtained by Feldner et al using plexin
A3 as well as semaphorin 3A morpholinos
(Feldner et al., 2007), as
well as by Tanaka et al. (Tanaka et al.,
2007). Although this does not exclude the co-existence of a
chemoattractive mechanism, our results present compelling genetic evidence
that a particular guidance mechanism - repulsion - guides the intraspinal
migration of motor growth cones.
Our studies also reveal a later role for Plexin A3 in restricting axonal
branching. In sidetracked (plexin A3) mutants, branches
invaded the myotome prior to the time period when wild-type motor axons do
(Fig. 3F). This phenotype is
somewhat reminiscent of the behavior that mossy fibers display in plexin A4
mutant mice (Suto et al.,
2007). There, it has been proposed that plexin A4 prevents mossy
fibers from invading the entire CA3 region, thereby restricting them to a
narrow zone (Suto et al.,
2007). Thus, similar to the situation in the CNS,
sidetracked (plexin A3) signaling in the periphery appears
to be crucial in order to prevent precocious spreading of motor axonal
branches into future synaptic muscle fields, possibly coordinating pre- and
postsynaptic development.
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/134/18/3251/DC1
ACKNOWLEDGMENTS
We would like to thank V. Schneider and J. Birely for help with the in situ hybridizations; C. Moens (HHMI, WashU) for providing sema3Fa; and D. Gilmour (EMBL) for comments on the manuscript. We would also like to thank H. Tanaka and H. Okamoto for communicating unpublished results. This work was supported by grants from the American Heart Association (K.A.P.), the National Science Foundation (M.G.) and the National Institute of Health (M.G.).
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