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First published online 11 October 2006
doi: 10.1242/dev.02592
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Review |
Departamento de Neurobiología del Desarrollo, Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain.
* Author for correspondence (e-mail: bovolenta{at}cajal.csic.es)
Successful axon navigation depends on the competence of the axon growing tip to receive and integrate information provided by multiple, spatially organised molecular cues arranged along the axon trajectory. Several recent studies have raised the intriguing possibility that `morphogen' signalling, known to give cell-specific positional information during tissue patterning, is later used to provide part of this guidance information to the growth cone. How general this strategy is has now become apparent with new compelling evidence from the Wnt field, which shows that new ligand-receptor interactions underlie the evolutionary conserved role of the Wnt signalling cascade in the initiation, elongation and turning behaviour of the growth cone.
Introduction
The progressive specification of different tissues and organs occurring
during early embryonic development is coordinated by a limited number of cell
signalling molecules (known as morphogens) that belong to the hedgehog (Hh),
Transforming Growth Factor-ß (Tgfß), Fibroblast Growth Factor (Fgf)
and wingless (Wnt) families of secreted ligands. These ligands bind to
specific receptors and activate particular intracellular cascades that
ultimately control the transcription of target genes, thus influencing cell
fate and cell behaviour (for a review, see
Tabata and Takei, 2004
). The
function of these signalling pathways, however, is not limited to cell
specification, as there is increasing evidence that they are also necessary to
control cell proliferation, cell survival and cell movement, not only in
embryogenesis, but also in postnatal life during normal and pathological
conditions (Bovolenta and Marti,
2005). This is not particularly surprising as all of these
processes depend heavily on changes in gene expression. Axon guidance, by
contrast, has been considered for many years to depend on the competence of
the growth cone to interpret information provided by different ligand-receptor
signalling systems [i.e. Ephrins/Eph, Netrins/DCC/Unc5, Slits/Robo,
Semaphorins/Plexin/Neuropilin (reviewed by
Dickson, 2002)] and to rely
also on local changes of a few intracellular mediators, like cyclic
nucleotides (cAMP and cGMP) and Ca2+ ions, and on
phosphorylation-dependent changes of certain cytoskeletal proteins (reviewed
by Song and Poo, 1999). This
view has been recently expanded with the discovery that local translation
(reviewed by van Horck et al.,
2004), particularly of mRNA of cytoskeletal proteins
(Piper et al., 2006), as well
as protein degradation (reviewed by van
Horck et al., 2004) are important events for growth cone steering
in response to guidance cues. Moreover, the local internalisation of molecules
known for their activity as transcription factors also influences growth cone
movement via the phosphorylation of translational regulatory proteins
(Brunet et al., 2005). In this
changing scenario, the demonstration that morphogen signalling is used at late
stages of embryonic development to control both axon growth and directionality
(reviewed by Bovolenta, 2005;
Charron and Tessier-Lavigne,
2005) offers an additional exciting perspective on the mechanisms
that contribute to the establishment of brain connections. Thus, in
vertebrates, Shh, Bmp and Wnt signalling has been implicated in the guidance
of retina ganglion cell (RGC) axons and of commissural axons of the spinal
cord (Augsburger et al., 1999;
Trousse et al., 2001;
Butler and Dodd, 2003;
Charron et al., 2003;
Lyuksyutova et al., 2003;
Bourikas et al., 2005).
These studies have raised an obvious question: is morphogen signalling at
the growth cone a general strategy for axon guidance? Very recent work in
Drosophila, C. elegans and vertebrates demonstrates that Wnt-mediated
signalling at the growth cone is indeed a general and evolutionary conserved
mechanism of axon guidance. Here, we review this new evidence and focus on new
ligand-receptor interactions that underlie the functions of the already
complex Wnt signalling pathways in axon guidance. Recent discoveries show that
Wnt-induced axon guidance is mediated by at least two different families of
receptors: the `classical' Frizzled receptors (Fz)
(Lyuksyutova et al., 2003;
Schmitt et al., 2005;
Sato et al., 2006;
Pan et al., 2006;
Hilliard and Bargmann, 2006;
Prasad and Clark, 2006) and
the newly identified atypical Tyr-kinase receptors, Derailed/Ryk (Related to
Tyrosine Kinase) (Yoshikawa et al.,
2003; Lu et al.,
2004; Liu et al.,
2005; Schmitt et al.,
2005). Whereas Fz receptors appear to mediate mainly attractive
responses of the growth cones to Wnts
(Lyuksyutova et al., 2003;
Schmitt et al., 2005;
Sato et al., 2006),
Derailed/Ryk mediates the repulsive ones
(Yoshikawa et al., 2003;
Liu et al., 2005;
Schmitt et al., 2005).
Furthermore, Secreted Frizzled Related Protein 1 (Sfrp1), an extracellular
modulator of Wnt signalling, also provides Wnt-independent guidance
information by binding to Fz2 (Rodriguez
et al., 2005). Thus, the same family of ligands (Wnt) can bind to
different receptor families (Fz, Ryk), and different ligands (Wnt, Sfrp) can
bind to the same family of receptors (Fz), all providing information to the
growing axons.
The Wnt signalling pathways
WNTs comprise a large family of lipid-modified, secreted glycoproteins that
are involved in cell-to-cell communication during the embryonic development of
different tissues, including the nervous system. By binding to the Fz
receptors (seven-pass transmembrane proteins with characteristics of G-protein
couple receptors), Wnts activate at least three different signalling pathways:
the canonical or Wnt/ß-catenin pathway, the planar cell polarity (PCP)
pathway and the Wnt/calcium pathway. In addition, as we discuss later, Wnt can
bind to Ryk/Derailed, which, in turn, can interact with Fz
(Lu et al., 2004). There are
many excellent and up-to-date reviews describing in detail these pathways
(Logan and Nusse, 2004;
Ciani and Salinas, 2005;
Kohn and Moon, 2005;
Cadigan and Liu, 2006;
Willert and Jones, 2006),
thus, we will just briefly describe their main features here.
A common step in the activation of all these three cascades is the
Fz-mediated recruitment of Dishevelled (Dvl), a cytoplasmic scaffold protein
with three conserved domains that mediates its interactions with different
proteins (reviewed by Wallingford and
Habas, 2005). In the canonical pathway, Dvl activation results in
the inhibition of Glycogen Synthase Kinase 3 ß (Gsk3ß), a
serine/threonine kinase that has multiple substrates, including ß-catenin
and microtubule-associated proteins (MAPs). In the absence of a Wnt stimulus,
Gsk3ß forms a complex with the scaffold protein Axin and the tumor
suppressor protein adenomatous polyposis coli (Apc), and recruits
ß-catenin, targeting it for degradation. Wnt/Fz interaction leads to the
disintegration of the Gsk3ß/Axin/Apc complex, with the consequent
accumulation of ß-catenin in the cytoplasm and its translocation to the
nucleus, where, in association with the T-cell factor/lymphoid-enhancer factor
(Tcf/Lef), it activates the transcription of target genes. At the cell
membrane, the activation of this pathway also involves the interaction of Fz
receptors with Arrow/low-density lipoprotein receptor-related protein 5 (Lrp5)
and Lrp6, which function as co-receptors
(Fig. 1A).
The alternative Wnt/Ca2+ and PCP pathways are less well
understood, but both are linked to the regulation of cell movement, including
the coordinated orientation of cells within an epithelium, the orientation of
stereocilia in the mammalian inner ear and the convergent extension movements
that occur during gastrulation (Veeman et
al., 2003). In the PCP pathway
(Fig. 1B), a Wnt-Fz interaction
leads to the Dvl-mediated activation of the small GTPases RhoA and Rok (Rho
kinase), or of Rac and c-Jun amino (N)-terminal kinase (JNK), which in turn
affects the dynamics of the cytoskeleton
(Fig. 1B). The
Wnt/Ca2+ pathway (Fig.
1C) involves G proteins, phospholipase C (PLC), phosphodiesterase
(PDE) and the activation of the Ca2+/calmodulin-dependent protein
kinase II (CaMKII), protein kinase C (PKC), calcineurin and the nuclear factor
of activated T cells (NF-AT).
Biochemical and genetic studies support the existence of antagonistic
crosstalk between the Wnt canonical and non-canonical pathway in different
contexts (Kohn and Moon,
2005). Furthermore, the activity of the three Wnt signalling
cascades is potentially modulated extracellularly by different Wnt
antagonists, including Wif1 (Wnt inhibitory factor 1), Cerberus, and members
of the Dickkopf and Sfrp families. Although Dickkopf proteins interfere with
Wnt activity by binding to Lrp5/Lrp6, thus antagonising canonical signalling,
Wif1, Cerberus and Sfrps can interact directly with Wnt proteins (reviewed by
Kawano and Kypta, 2003), and,
thus, can potentially interfere with all three signalling pathways. Notably,
Wif1 shares structural similarity with the Ryk receptor, whereas Sfrps are
modular proteins that fold into two independent domains
(Chong et al., 2002), one of
which is structurally related to the Cysteine Rich Domain (CRD) of Fz
receptors. The other Sfrp domain, known as Netrin module (NTR), is
characterised by a set of conserved disulfide bridges and by segments of
hydrophobic residues that have been identified in several other proteins,
including Netrin 1 (Banyai and Patthy,
1999). Possibly as a result of this modular structure, Sfrps
appear to have Wnt-independent mechanisms of action
(Kawano and Kypta, 2003),
including a direct interaction with Fz
(Bafico et al., 1999;
Rodriguez et al., 2005) and
being able to interfere with Bmp signalling
(Lee et al., 2006b;
Muraoka et al., 2006).
|
;
Ciani et al., 2004).
Furthermore, the Wnt/Ca2+ pathway has interesting similarities with
the pathway triggered by the activation of other G-protein coupled receptors
(GPCR), which has recently been shown to be involved in axon guidance
(Xiang et al., 2002),
suggesting that different mechanisms of action could be expected. A conserved role for Wnt signalling in axon guidance
The first evidence of the involvement of the Wnt pathway in axon guidance
came from studies of the central nerve cord of Drosophila
(Fradkin et al., 1995). This
system has also been instrumental in identifying Derailed/Ryk as the receptor
that mediates Wnt-induced growth cone repulsion
(Yoshikawa et al., 2003), thus
defining a new ligand-receptor signalling system for the guidance of
axons.
In each segment of the Drosophila ventral nerve cord, commissural
axons cross the midline, selecting either the anterior (AC) or posterior (PC)
commissural tract. Wnt5, also known as Dwnt3, is strongly expressed in cells
positioned ventrally to the PC (Fig.
2A). If this localised production of Wnt5 is disrupted by
ubiquitous overexpression, commissural tracts do not form properly
(Fradkin et al., 1995).
Derailed (drl), an atypical receptor tyrosine kinase
initially unrelated to Wnt activity, is normally expressed in the axons of AC
projecting neurons (Fig. 2A).
In drl null mutants, AC axons abnormally cross into the PC, whereas
the misexpression of drl in PC neurons conversely forces their axons
through the AC (Fig. 2B)
(Callahan et al., 1995;
Bonkowsky et al., 1999). A
genetic screen for mutations that suppress this last phenotype brought the
observations of these two studies together, identifying Wnt5 as a ligand for
Drl and as an essential cue for the proper projection of AC axons
(Fig. 2C)
(Yoshikawa et al., 2003). More
precisely, Wnt5 repels AC growth cones that express Drl. drl does not
show genetic interaction with Dfz1 (fz - FlyBase) and
Dfz2 (fz2 - FlyBase), suggesting that Drl-mediated,
Wnt5-induced repulsion is independent of Fz. Rather, Wnt5 signalling seems to
require the intracellular domain of Drl, because misexpression of its
truncated version in PC cells fails to cause PC axons to cross through the AC
(Yoshikawa et al., 2003).
Furthermore, Wnt5 might have additional functions during the formation of the
Drosophila nerve cord. In wnt5 null mutants, AC and PC do
not separate properly, and `fuzzy' commissures are formed. Even more
intriguingly, Wnt5 expression in AC neurons might be negatively controlled by
Drl itself, as there is a twofold increase in Wnt5 protein levels in
drl mutants (Fradkin et al.,
2004).
|
), a
structure that is the possible vertebrate equivalent of the
Drosophila nerve cord. Two Wnt molecules, Wnt1 and Wnt5a, are
expressed in an anterior-high, posterior-low gradient along the length of the
mouse dorsal spinal cord, coinciding with the trajectory of the descending
motor cortico-spinal axons, which express Ryk on their surface. In collagen
gel experiments, Wnt1- or Wnt5a-transfected cells (but not cells transfected
with other Wnts) strongly inhibit neurite outgrowth from neonatal, but not
embryonic motor cortex explants, suggesting that cortico-motor axons become
receptive to Wnt activity at the time when they normally reach the spinal
cord. This effect is mimicked by co-cultures with anterior, but less so with
posterior, dorsal spinal cord explants, and is abolished by antibodies against
Ryk, indicating that Ryk mediates the effect of a graded diffusible
chemo-repellent(s) (probably Wnt1 and/or Wnt5) that forces the growth of
cortico-spinal axons down the spinal cord
(Liu et al., 2005). In
agreement with this interpretation, intrathecal injections of anti-Ryk
antibodies reduce the growth of cortico-spinal axons posterior to the site of
injections (Fig. 2E).
Biochemical studies have indirectly excluded Fz participation in this activity
(Liu et al., 2005;
Schmitt et al., 2005).
Thus, in both vertebrates and invertebrates, a Fz-independent, Wnt-Ryk/Drl
interaction functions as a negative regulator of axon growth. However, in the
case of the vertebrate cortico-spinal tract, the mechanism appears to be
counterintuitive, as one would expect axon growth to stall when they encounter
a strong repellent activity. A strictly time-regulated expression of Ryk at
the axon surface, as indicated by the differential sensibility to Wnts
observed in embryonic and postnatal cortical explants
(Liu et al., 2005), might
explain this apparent paradox. Alternatively, counteracting attractive forces
emanating from the caudal spinal cord could counterbalance the repellent
activity, as has been suggested for the possible cooperation of the opposite
Wnt4 and Shh gradients in the rostral growth of commissural axons
(Stoeckli, 2006). On
commissural axons, however, Wnt exerts an attractive force, offering the first
vertebrate example of a positive Wnt-induced guidance activity, probably
mediated by a Fz receptor (Fig.
3A) (Luksyutova et al., 2003).
|
). A search for molecules that could favour the rostral growth
of commissural axons has identified several Wnts (Wnt1, Wnt4, Wnt5a, Wnt6,
Wnt7b) as being the best candidates for this activity (Luksyutova et al.,
2003). Among these, only Wnt4 fulfils the necessary physiological condition
for this activity: an anterior-high to posterior-low graded distribution at
the floor plate, a prerequisite previously determined with a series of clever
in vitro tissue recombination experiments
(Fig. 3B,C) (Luksyutova et al.,
2003). Interestingly, commissural axons in Fz3 null mouse embryos
grow normally towards the midline but, after crossing the floor plate, project
randomly along the anteroposterior (AP) axis, suggesting that Wnt4 activity
might be mediated by the Fz3 receptor (Luksyutova et al., 2003).
A low concentration of Wnt, specifically Wnt3a, provides similar
Fz-mediated, positive guidance information to chick dorsal (but not ventral)
retina ganglion cell (RGC) axons that project to the tectum. In addition, high
concentrations of Wnt3a strongly inhibit dorsal, as well as ventral, RGC axon
outgrowth (Schmitt et al.,
2005). The physiological significance of this observation resides
in the graded distribution of Wnt3a, which decreases in a
medio(dorso)-lateral(ventral) direction in the chick optic tectum and in the
mouse superior colliculus. Normally retinal projections to the tectum (or
superior colliculus) are spatially organised: ventral retinal axons project to
the medial tectum, whereas dorsal axons terminate in the lateral tectum. This
organisation is in part dictated by an attractive force provided by the EphB
receptor tyrosine kinases and their EphrinB ligands, well recognised axon
guidance cues with a crucial role in the establishment of topographic
projections in the visual system
(McLaughlin and O'Leary,
2005). However, modelling studies have suggested the need for a
repellent gradient in the same direction, as a possible mechanism to achieve
precise topography (Hindges et al.,
2002). With a series of in vitro and in ovo experiments
(Fig. 4A), Schmitt and
colleagues (Schmitt et al.,
2005) reached the conclusion that Wnt3a could be this additional
cue, acting through two different receptors: Fz, which is uniformly
distributed in RGC throughout the retina; and Ryk, which strongly localises to
the ventral RGC. Thus, Ryk-positive, ventral RGC axons are repelled by Wnt3a,
whereas Fz receptors mediate the attractive response of dorsal RGC axons to
low concentrations of Wnt3a. In this light, retinotopic organisation in the
mediolateral axis, as well as growth of axon branches, would result from the
competition between a repulsive Ryk-mediated signal and an attractive
Fz-mediated signal derived from different concentrations of the same ligand,
Wnt3a (Fig. 4A)
(Schmitt et al., 2005).
Part of this signalling system is conserved in invertebrates to regulate
the dorsoventral (DV) organisation of Drosophila visual projections
to the first optic ganglion, the lamina
(Sato et al., 2006). In the
fly, retina R1-R6 photoreceptors project to the lamina with a precise
organisation along the AP and DV axes. Dwnt4 (Wnt4 - FlyBase) is
expressed asymmetrically only in the ventral lamina, where ventral retinal
axons terminate (Fig. 4B). If
this asymmetry is disrupted by either Dwnt4 loss-of-function or by
ectopic expression of Dwnt4 in the dorsal lamina, ventral axons
mis-project to the dorsal lamina (Fig.
4B), indicating that Dwnt4 normally acts as a cue for ventrally
projecting photoreceptors (Sato et al.,
2006). The inhibition of non-canonical pathway components,
including Dfz2, Dvl and hemipterous, the Drosophila homologue of JNK,
strongly interferes with ventral photoreceptor axon projections, indicating
that this pathway is likely to mediate Dwnt4 activity. Intriguingly,
the specificity of the retinal projections to the lamina appears to be
reinforced by the activity of iroquois (iro), a homeobox
gene that confers dorsal identity to the retina. In iro mutants,
dorsal axons accumulate Dwnt4 and mis-project to the ventral lamina. This
phenotype is suppressed in iro;Dfz2 double mutants, suggesting that
iro may attenuate the competence of Dfz2 to respond to Dwnt4
(Sato et al., 2006).
|
;
Hilliard and Bargmann, 2006;
Prasad and Clark, 2006). In
addition, these studies have shown that this signalling also influences AP
neuronal polarity and, thus, the characteristics of neuronal processes
(Hilliard and Bargmann, 2006;
Prasad and Clark, 2006).
In the C. elegans embryo, egl-20(wnt) is expressed in the
tail (Fig. 5A), behind the
anterior (AVM) and posterior (PVM) ventral mechanosensory neurons. These
neurons grow a single process that extends ventrally, enters the nerve cord
and then turns anteriorly (Fig.
5B). In embryos mutants for two Wnt genes (cwn-1;egl-20)
or two frizzled receptors (mig-1;mom-5), AVM and PVM axons join the
ventral nerve cord as normal but then present variable pathfinding defects:
they stall, turn in the posterior direction or bifurcate, sending anterior and
posterior processes (Fig. 5C),
indicating that Wnt/Fz are required to direct growth cones in the anterior
direction (Pan et al., 2006;
Prasad and Clark, 2006).
Ectopic overexpression of egl-20(wnt) in the posterior region of
cwn-1;egl-20 double-mutant animals significantly rescues the
mutant phenotype, whereas a similar ectopic expression in the anterior
position enhances the pathfinding defects. The phenotype induced by the
anterior misexpression of egl-20(wnt) is reduced in Fz double mutants
(mig-1;mom-5), whereas posterior ectopic expression of
egl-20(wnt) does not rescue the Fz double mutant phenotype.
|
;
Prasad and Clark, 2006), or
after ectopic expression of egl-20 anterior to the ring
(Pan et al., 2006).
Furthermore, simultaneous inactivation of either cwn-1;egl-20 or
cwn-1;cwn-2 interferes with the proper establishment of ALM
anteroposterior polarity. Strong polarisation defects are also observed in the
PLM processes of Fz(Lin-44) mutants alone, or combined with the
cwn-1 or egl-20 Wnt mutants
(Prasad and Clark, 2006). In summary, in C. elegans, Wnt-Fz interaction is required to establish the proper polarisation of specific neurons and, in contrast to the attractive information observed in the fly and vertebrates, provides a repellent signal that forces mechanosensory axons to grow in the anterior direction.
Additional functions of Fz or Ryk in axon guidance
The work described above strongly supports that Wnt-Ryk and Wnt-Fz are
ligand-receptor pairs with a conserved role in neuronal process development
(Table 1). However, there are
additional examples in vertebrates that illustrate the importance of Ryk or Fz
as mediators of axon guidance cues. In Ryk null mice, cortical axons
grow through the corpus callosum in a defasciculated manner and stall at the
contralateral side without reaching their targets. Wnt5a, which is expressed
in the surrounding of the corpus callosum, inhibits the extension of embryonic
cortical axons in explant cultures and interacts with Ryk in vitro, indicating
that additional chemorepulsive information is provided by the Wnt/Ryk
interaction (Keeble et al.,
2006). Furthermore, inactivation of Fz3 in mice causes
the absence of, or a great reduction in, several axon tracts, including the
anterior commissure, cortico-spinal tract, corpus callosum, fornix,
thalamo-cortical and cortico-thalamic tracts, stria medullaris, stria
terminalis and hippocampal commissure
(Wang et al., 2002;
Wang et al., 2006).
Interestingly, Fz3 is co-expressed in striatal and thalamic cells
with Celsr3 (Tissir et al.,
2005), an ortholog of the Drosophila flamingo, a
protocadherin involved in PCP. Mice defective in Celsr3 show defects
in thalamo-cortical connectivity that are similar to those observed in
Fz3-/- mice (Wang et
al., 2002; Tissir et al.,
2005), further associating genes involved in PCP with axon
guidance.
|
; Keeble et al.,
2006). Similar considerations apply to Wnt3a in the chick visual
system (Schmitt et al., 2005).
This is not a peculiarity of Wnt proteins, as analogous situations exist for
Shh and Netrins. Shh-induced attraction of pre-crossing commissural axons is
presumably mediated by the Smoothened receptor
(Charron et al., 2003),
whereas Hip (Hedgehog Interacting Protein) is involved in Shh-induced
repulsion of post-crossing commissural axons
(Bourikas et al., 2005). Unc5
conveys Netrin1-induced repulsion in both vertebrates and invertebrates,
whereas Dcc (Deleted in Colorectal Cancer) can mediate both positive and
negative Netrin1 signalling, but, in the latter case, by forming a complex
with Unc5 (reviewed by Chilton,
2006). An interaction between Ryk and Fz has been also reported.
In co-immunoprecipitation assays, Ryk interacts with Dvl, and with both Wnt
and Fz; furthermore, interfering with Ryk expression in vitro abolishes
Wnt3a-induced neurite outgrowth from DRG explants, suggesting that when
interacting with Fz, Ryk can enhance axon growth
(Lu et al., 2004).
With this one exception, most studies, however, suggest that Wnt-Ryk and
Wnt-Fz signalling at the growth cone are independent. This seems to be the
case in the Drosophila nerve cord
(Yoshikawa et al., 2003) and
is particularly evident in the vertebrate visual system. Indeed, binding
assays demonstrate that anti-Ryk antibody can block Wnt-Ryk, but not Wnt-Fz,
binding; by contrast, Sfrp2, an extracellular modulator of Wnts, can partially
block Wnt-Fz, but not Wnt-Ryk, binding. Consistent with this, Sfrp2, but not
Ryk antibodies, block Wnt3a-induced axon outgrowth from the dorsal retina.
Conversely, anti-Ryk antibodies, but not Sfrp2, interfere with the axon
outgrowth inhibition caused by Wnt3a on the ventral retina
(Schmitt et al., 2005).
Similarly, Sfrp2 does not prevent Wnt-Ryk-mediated repulsion on cortico-spinal
axons (Liu et al., 2005).
Besides indicating that Ryk and Fz function independently, these studies
also indicate that different Wnt domains are involved in the binding of Wnts
to Ryk or Fz. In the most common model, Wnts bind to either Fz or Sfrps
through their respective CRD domains. In this way, Sfrps sequester Wnts in the
extracellular space by competing with Fz
(Kawano and Kypta, 2003). The
domain of Wnt that interacts with Fz or Sfrps is undefined but clearly has to
be different from that mediating Wnt binding to Ryk, given the null effect of
Sfrp2 on Ryk-mediated Wnt3a activity
(Schmitt et al., 2005).
Alternatively, Sfrp2 could block Wnt-mediated axon outgrowth by binding to the
Fz receptor. This possibility is supported by in vitro studies that
demonstrate a direct binding of Sfrps to Fz
(Bafico et al., 1999;
Rodriguez et al., 2005), and
by the observation that interference with Fz2 expression abolishes
the Wnt-independent activity of Sfrp1 on RGC growth cone movement, thus
pointing to a new ligand for Fz in axon guidance
(Rodriguez et al., 2005).
Indeed, in different vertebrates, Sfrp1 is strongly expressed in
crucial regions of the initial visual pathway, including the optic nerve head,
the chiasm and the initial portion of the optic tract. Consistent with this
distribution, interfering with normal Sfrp1 levels disrupts the growth of
Xenopus RGC axons along the optic tract. Notably, Sfrp1 causes RGC
growth cones to undergo a bi-functional chemotropic turning response, when
tested in stripe and turning assays, depending on its interaction with
extracellular matrix (ECM) molecules
(Rodriguez et al., 2005).
Similar to what is observed with Netrin1
(Hopker et al., 1999),
Sfrp1-laminin combinations result in RGC axons showing a strong repulsion
behaviour, whereas Sfrp1-fibronectin pairs induce growth cone attraction
(Rodriguez et al., 2005). Fz2
is required for the Sfrp1-laminin response
(Rodriguez et al., 2005), but
whether it mediates Sfrp1-fibronectin induced attraction still needs to be
determined.
In conclusion, it seems that the Wnt-Ryk interaction has a conserved
function in mediating only repulsive information at the growth cone. By
contrast, Fz receptors appear to be less `strict': they mediate both positive
and negative axon guidance information and can bind different ligands,
including Wnts, Sfrps and norrin, a protein involved in an X-linked congenital
retinal dysplasia that is structurally unrelated to Wnts
(Xu et al., 2004). Whether
different Fz subtypes (i.e. Fz3 versus Fz2) have specific preferences for
different ligands or whether additional components (i.e. ECM molecules or Ryk
interaction) can modulate Fz-mediated responses needs to be established.
Cascades downstream of Fz- and Ryk-mediated axon guidance
Even though it is clear that Fz and Ryk have important functions in the
initiation, elongation and turning of the axon of different neuron types, it
is still unclear how they transduce information from the surface to the other
growth cone components, particularly the cytoskeleton, to modify their
behaviour. This is especially true for Ryk, which is an atypical tyrosine
kinase receptor that lacks intrinsic catalytic activity; it is therefore
unclear what mechanism is used for signal transduction. One interesting
possibility is its reported association with the EphB receptors
(Fig. 6)
(Trivier and Ganesan, 2002),
the loss of which causes defects similar to those described for the Ryk null
mice (Halford et al., 2000). A
connection between the two systems may be Dvl, which seems to interact with
both Ryk and EphrinB1 (Lu et al.,
2004; Lee et al.,
2006a). In addition, interaction between Ryk and Fz has been
reported, suggesting that the two proteins may form a multi-receptor complex
signalling through the canonical pathway
(Lu et al., 2004). Although
this may occur, the evidence derives mostly from in vitro overexpression
studies that need to be confirmed in different experimental contexts.
The Wnt-Fz signalling cascade has been extensively studied and, thus, there
are many more data pointing to the mechanisms that may mediate Fz functions in
axon guidance, but only one so far has provided direct evidence
(Sato et al., 2006). Most of
the other studies link Wnt signalling to cytoskeletal dynamics in different
contexts.
Of the three Wnt signalling cascades, the PCP and Wnt/calcium pathways are
the best candidates. Indeed, both pathways have been strongly involved in the
control of Wnt-induced cell migration, a process that has many similarities
with axon guidance. As mentioned earlier, the Wnt/calcium pathway has striking
similarities with that described for the activation of other GPCRs in axon
guidance, both involving pertussis toxin-sensitive G proteins, PKC, CamKII,
and the modulation of cytosolic levels of cGMP and Ca2+
(Slusarski et al., 1997;
Xiang et al., 2002).
Furthermore, components of both pathways, like the small GTPases RhoA and Rac,
or intracellular levels of Ca2+ and cyclic nucleotides, are
considered to be necessary pieces of the network that controls the response of
a growth cone to many different guidance cues
(Wen and Zheng, 2006). In
agreement with this idea, proteins involved in the PCP pathway, including JNK,
are required for Dwnt4-mediated retinotopic organisation in the fly
(Sato et al., 2006), and Rac
and JNK have been implicated in Wnt-induced dendrite morphogenesis acting
downstream of Dvl (Rosso et al.,
2005). A link between Dlv and Rho GTPase could be Daam1, a member
of the mammalian diaphanous-related formin family, which binds to both
proteins and mediates convergent extension movements during vertebrate
gastrulation (Habas et al.,
2001). An association among Wnt and Rho and Rok
(Veeman et al., 2003), a
kinase that indirectly regulates ADF/cofilin, a depolymerising actin factor,
has been also reported to control microfilament dynamics in other
developmental contexts (Maekawa et al.,
1999). Furthermore, overexpression of Fried, a protein tyrosine
phosphatase that interacts with the C-terminal PDZ domain of Fz8, reorganises
cortical actin in Xenopus ectoderm
(Itoh et al., 2005).
|
; Orme et al.,
2003; Rosso et al.,
2005; Veeman et al.,
2003), Dvl, Apc and Gsk3ß, which are involved in the initial
steps of the canonical pathway, are the main players.
During synaptogenesis, Wnt-Fz interaction leads to axonal remodelling via
the inhibition of Gsk3ß (Ciani and
Salinas, 2005), a kinase that phosphorylates
microtubule-associated proteins, including Tau
(Wagner et al., 1996), Map1B
(Microtubule Associated Protein 1B) (Lucas
et al., 1998), Apc (Zumbrunn
et al., 2001) and Crmp2 (Collapsin Response Mediator Protein 2)
(Yoshimura et al., 2005). The
phosphorylation state of these proteins is crucial for their binding to the
microtubules, and, therefore, Gsk3ß indirectly controls microtubule
dynamics. This activity also requires Dvl, which, through its PDZ domain
inhibits a Gsk3ß pool locally bound to microtubules
(Ciani et al., 2004;
Krylova et al., 2000).
Interestingly, a different Dvl domain, DIX, appears necessary for both actin
binding (Capelluto et al.,
2002) and neurite outgrowth
(Fan et al., 2004). Finally,
Apc may function as a link between microtubule and actin components, as its
binding affinity to either microtubules or the actin cytoskeleton changes
depending on its phosphorylation state
(Zhou et al., 2004;
Zumbrunn et al., 2001).
Thus, there is a strong case for a local activity of Wnt on the growth cone
(Fig. 6). By modifying
cytoskeleton dynamics, the Wnt-Fz signalling system could orient axons by
using mechanisms that are comparable to those adopted by other more
`traditional' guidance cues (Wen and
Zheng, 2006). This does not exclude that Fz and Ryk may also act
on the growth cone via gene transcription, local protein synthesis regulation
or the control of endocytic recycling
(Piper et al., 2005). In this
respect, retromer, a protein complex that mediates endosome-to-Golgi protein
trafficking, has been associated with the Wnt-induced establishment of
neuronal polarity in C. elegans
(Prasad and Clark, 2006).
Conclusion and perspectives
In conclusion, Fz and Ryk serve as receptors for a conserved class of axon
guidance cues: the morphogen Wnts. Generally, Fz receptors mediate attractive
responses, whereas Drl/Ryk is responsible for conveying repulsive information
to the growth cone. In addition, Fz can mediate the activity of Sfrp1, a Wnt
signalling modulator that, independently of Wnt, controls RGC growth cone
movements. It is possible that this last ligand-receptor pair might only
operate in vertebrates, as no clear homologues of Sfrps have been found among
invertebrates (Kawano and Kypta,
2003), although their modular structure may have complicated the
search.
In mammals, there are 19 Wnt genes, 10 Fz receptors, one Ryk, five Sfrps
and several possible signalling cascades, which are in constant expansion, as
recently indicated by the finding that Wnt can also operate through the
receptor tyrosine kinase-like orphan receptors (Ror), repressing
Wnt-ß-catenin signalling (Mikels and
Nusse, 2006). At the moment, there are perhaps more questions than
answers as to how this crowded scenario may fit into the control of axon
guidance. For example, a point to be resolved is the binding specificity of
all the receptor-ligand pairs. Wnts seems to have a greater affinity for Ryk
than for Fz (Liu et al.,
2005). Is this the case for all Wnt proteins? An answer to this
question should help to define relevant physiological situations, as is the
case for the ventral RGC, where Fz and Ryk compete for Wnt3a binding
(Liu et al., 2005). The
generation of appropriately engineered Wnt mouse mutants should also give
important information, as the mutants currently available have not been
reported to show major alterations in axon tract formation, suggesting that
Ryk and Fz in vivo may be activated by multiple ligands.
Many other, and possibly more general, questions come to mind. Where are
Wnt proteins really localised? As most of our information on Wnt distribution
comes from in situ hybridisation studies, this question remains open. How far
do Wnts (or other morphogens involved in axon guidance) diffuse? Is there a
differential distribution of receptors along the axon or the growth cone? How
is the timing of receptor expression regulated? This is a crucial point to
understand; for instance, why pre-crossing commissural axons are insensitive
to the Wnt4-attractive gradient at the ipsilateral side of the floor plate.
The example of the Eph2A receptor, which is locally translated in the
commissural growth cones as they cross the midline
(Brittis et al., 2002), offers
an attractive example of how sensitivity to Wnt4 could be regulated.
Alternatively, as in RGC, Sfrp1, strongly expressed in the ventral midline
(Esteve et al., 2000), may
provide guidance information to commissural axons at the ipsilateral side by
binding to Fz, thus temporarily excluding it from Wnt binding.
Specific experiments are needed to answer these hypotheses. Because Wnt signalling pathways are involved in many different biological processes (from development to disease), advances in this field may provide useful information in other contexts where Wnt-Fz, Fz-Sfrp or Ryk-Wnt interactions might also be relevant.
ACKNOWLEDGMENTS
Work in our laboratory is supported by grants from Spanish Ministerio de Educación y Ciencia, Fundación `la Caixa' and Fundación Mutual Madrileña to P.B. J.R. is supported by a Glaxo-CSIC fellowship and P.E. holds a contract of the `Ramon y Cajal Programme' of the Spanish Ministerio de Educación y Ciencia.
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This article has been cited by other articles:
,ß,
, G-protein subunits; Apc, adenomatous polyposis
coli; CamKII, calcium/calmodulin-dependent protein kinase II; Daam1,
dishevelled associated activator of morphogenesis 1; DAG, diacylglycerol; Dvl,
dishevelled; Fz, Frizzled receptor; Gsk3ß, glycogen synthetase kinase 3;
IP3, inositol 1,4,5-trisphosphate receptor; JNK, jun kinase; Lrp, low-density
lipoprotein receptor-related protein; Map1B, microtubule-associated protein
1B; NF-AT, nuclear factor of activated T cells; PIP2,
phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PLC,
phospholipase C; Rok, Rho kinase; Ryk, receptor-like tyrosine kinase; Tcf,
T-cell factor.
