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Role of Semaphorins during Axon Growth and Guidance

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Introduction

During development, neuronal growth cones navigate over long distances to reach their target and establish appropriate connections. This process is usually described as a step by step mechanism of growth recruiting several guidance cues with attractive and repulsive properties. Among these signals, the semaphorins define a large family of more than twenty members divided into eight classes according to their phylogenic relationship and the existence of differential structural domains or sequence motifs1 (Fig. 1). Classes I and II are found in invertebrates and classes III, IV and VII in vertebrates while class V contains members from both vertebrates and invertebrates. The class VIII corresponds to viral semaphorins. Semaphorins can be soluble proteins (classes II and III), transmembrane proteins (classes I, IV, V and VI) or membrane-bound through a glycosylphosphatidylinositol anchor (class VII). Together with plexins and scatter factor receptors, semaphorins belong to the semaphorin superfamily whose defining feature is the existence of a conserved domain: the semaphorin domain. This domain of more than 500 amino acids located at the mature protein N-terminus was first identified by Kolodkin and collaborators in 1993.2 All semaphorins also contain N-glycosylation sites and their C-terminal part is differing from one class to another. Indeed, class V contains seven copies of thrombospondin repeats, classes II-V and VII contain an immunoglobulin-like domain while class III has an N-terminus basic motif. Semaphorins are widely expressed in the developing nervous system. Initially described as guidance cues ensuring axon targeting, further studies showed that they are also key regulators of cell migration, cell death or synapse formation during nervous system development. Like other guidance cues, semaphorins are also clearly implicated in various aspects of organogenesis3 (including lung and kidney formation or angiogenesis) and during tumor progression.4 Here, we review the major functions of semaphorins in the nervous system together with the signaling mechanisms involved both at the level of receptor complex formation and recruitment of selective intracellular pathways.

Figure 1. Semaphorin family (adapted from Unified nomenclature of semaphorins, Cell 1999).

Figure 1

Semaphorin family (adapted from Unified nomenclature of semaphorins, Cell 1999).

Functional Roles of Semaphorins during Axon Guidance

The most studied semaphorin is certainly the soluble Sema3A. The first functional description was the ability of Sema3A to act as a repulsive factor on chicken DRG neurons by inducing the collapse and retraction of their growth cones.5 Further studies showed a repulsive effect of Sema3A on other neuronal cells, such as sensory, sympathetic and cortical neurons (Table 1 and for review see ref. 6). Most of the semaphorins identified so far mediate axon repulsion. Strikingly some members have a growth promoting effect on specific neuronal subpopulations. This is the case of Sema3C that promotes the growth of cortical axons7 and Sema3F that promotes the growth of olfactory bulb axons.8 In vivo experiments conducted in the zebrafish showed that Sema3D triggered attraction or repulsion depending on a differential recruitment of receptor subunits.9 In this study, a receptor complex composed of neuropilin-1 (NRP1) induced repulsion of commissural axons whereas a heterodimer composed of the two class III semaphorin receptors (neuropilin-1 and -2) triggered attraction of these axons. Thus, the temporal regulation of semaphorins and/or their receptors expression is of crucial importance to determine their functions. For example, Sema3A is expressed in the olfactory bulb from E5 to E7 in the chick when axons begin to invade the telencephalum. At E9, when axons enter the olfactory bulb, this expression is reduced.10 Similarly, during the development of the limb innervation by the peripheral nervous system, the target limb expresses Sema3A at early time points (E10.5 in mice) thereby preventing growth cones of neuropilin-expressing motor neurons to enter this region. At E12.5 this inhibitory barrier disappears and the limb becomes permissive for the axons destined to synapse there. Again, a differential expression of semaphorin receptors contributes to the segregation of these axons since the NRP2-expressing growth cones are repelled by the Sema3F-containing dorsal limb region and redirected towards the ventral part of the limb while growth cones lacking NRP2 innervate the dorsal part of the limb.11

The genetic analysis of semaphorin function revealed several defects such as abnormal projections of sensory axons, abnormal cortical neurites orientation12 or distorted odor map13 in Sema3A-deficient mice. In many cases, the most severe phenotype was the defasciculation of axonal tracts in absence of Sema3A signaling.14,15 These results are consistent with in vitro studies that have demonstrated how the inhibitory environment produced by Sema3A along cortical efferent and afferent pathways forces the axons to fasciculate.16 Several defects in projections in the hippocampus, mid brain, forebrain and in the PNS of Sema3F deficient-mice have also been described.17 The diversity of the guidance effects triggered by semaphorins is therefore consistent with their role in the complex wiring of various brain regions. In the cortex, a combination of Sema3A (acting as a repellent for axons and attractant for dendrites) and Sema3C (acting as a chemoattractant) is thought to control the establishment of the cortical efferent projections7,18 and apical dendrites development.19 Multiple combinations of semaphorins participate in the construction of axonal projections in the hippocampus,20-22 the olfactory bulb,8 the thalamus,16 the spinal cord11,23 or in the peripheral system.14 Recently, it has been shown that not only neurons are sensitive to semaphorins in the nervous system, but also glial cells and particularly oligodendrocytes, which express semaphorin receptors. In vitro experiments showed that class 3 semaphorins control oligodendrocytes outgrowth24,25 and are able to induce the collapse of their growth cones.26 Oligodendrocytes migration is also controlled by class 3 semaphorin27 and a comparable function in cell migration has been described for Sema3A and Sema3F that have been shown to differentially guide subtypes of GABAergic neurons to their appropriate target in the cortical plate or intermediate zone.28 While the strongest expression of semaphorin is observed during development, some regions such as the hippocampus or the olfactory bulb continue to express semaphorins in adulthood.29,30 This expression in regions presenting high level of network remodeling is consistent with evidence implicating class 3 semaphorins in the modulation of the synaptic function in the hippocampus.31,32 These regions are also known to maintain a neurogenic potential33-35 thereby suggesting that the role of the semaphorins in the nervous system is certainly more complex than initially thought. Indeed, some of the semaphorins have been shown to induce cell death of dopaminergic and sensory neurons36 as well as neural precursors.37 Hence, there is also increasing evidence for a potential role of semaphorin signaling in different pathologies of the nervous system. For example, Sema3A is over-expressed in the cerebellum of schizophrenic patients.38 Sema3A is also accumulated in the hippocampus during Alzheimer disease.39 In a rat model of temporal lobe epilepsy, Sema3A is down-regulated thereby permitting mossy fibers sprouting and subsequent hyper excitability of the hippocampal formation.40 Finally, the role of class 3 semaphorins in the context of nerve lesion has also been largely documented.41,42

From these results, it appears that semaphorins have multiple roles ranging from axon guidance (attraction or repulsion) to cell migration or cell death. This functional diversity must be ensured by a complex signaling mechanism recruiting various receptors and co receptors coupled to specific intracellular pathways. In the following section, we will present the different families of semaphorin receptors and their interactions (Fig. 3).

Receptors of Secreted-Semaphorins: The Neuropilins

The molecular nature of semaphorin receptors remained elusive for many years until the identification of neuropilin-1 as a membrane receptor for the secreted Sema3A.43,44 Neuropilin-1 was initially described by Fujisawa and colleagues as an orphan receptor expressed in the tadpole neuropil.45,46 During a search for other semaphorin receptors, a neuropilin-1-related molecule, neuropilin-2, was identified.44,47 Neuropilin-2 is 44% identical to neuropilin-1. Neuropilins are cell surface glycoproteins of about 130 kD (Fig. 2). They are composed of a large extracellular part, a unique transmembrane domain and a small 39 amino acid cytoplasmic tail. The extracellular moiety of neuropilins contains three domains with homology to several functionally diverse proteins. The N-terminus domain is referred to as the a1/a2 or CUB domain with homology to complement components C1r and C1s, this domain is followed by two coagulation-factor-homology domains (CF V/VIII, also called b1/b2) and a juxtamembrane MAM (meprin/A5/μ-phosphatase) domain also called c domain. The C-terminal part of neuropilins contains a three amino acids sequence which might bind to PDZ domain proteins such as NIP (Neuropilin Interacting Protein).48 NRP1 or NRP2 have to dimerize to form a functional receptor complex. They can both form homo- or heterodimers44 involving the MAM domains.29,49,50 Our recent data suggest that the transmembrane domain of NRP1 contains a specific motif ensuring NRP1 dimerization (unpublished data, Roth and Bagnard). The constitution of homo- or heterodimers is considered to be a prerequisite for semaphorin binding. Indeed, binding experiments revealed that Sema3A may preferentially bind to NRP1 dimers, Sema3F to NRP2 dimers while Sema3C would bind to NRP1 as well as to homo or heterodimers of NRP2. Dimerization is also required at the level of ligand since to be functional, class III semaphorins dimerize through a disulfide bound located between the immunoglobulin (Ig) domain and their basic tail.51,52 Overall, a model for the semaphorin/neuropilin complex has been proposed by several groups.43,53-55 In this model, a semaphorin dimer binds to a neuropilin dimer on the cell surface. More precisely, the binding interface is composed of the sema domain's N-terminal part and Ig domain of semaphorins interacting with the neuropilin CUB domain while the basic C-terminal part of semaphorins bind to the coagulation factor domains of neuropilins. High affinity binding of the semaphorin Ig-basic region to the coagulation factor domains is itself not sufficient for signal transduction. Rather, it is considered to facilitate binding of the sema domain to CUB and coagulation factor domains. Interestingly, the MAM domain is not involved in the semaphorin/neuropilin interaction. The most striking feature of semaphorin/neuropilin interaction is the lack of transduction capacity supposedly due to the short intracellular tail of NRP1. The role of NRP1 and NRP2 for semaphorin signaling has been clearly shown in experiments mutating the corresponding genes14,56,57 suggesting that the semaphorin/neuropilin interaction is the initial step for the assembly of a receptor complex recruiting transducing elements. Among the multiple possible partners that have been identified recently, members of the plexin family are crucial components of the receptor complex. Interestingly, the plexins are the binding receptor of transmembrane semaphorins.

Figure 2. Characteristic features of the two major semaphorin receptors.

Figure 2

Characteristic features of the two major semaphorin receptors.

Figure 3. Molecular diversity of semaphorin receptor complexes.

Figure 3

Molecular diversity of semaphorin receptor complexes.

Receptors of Transmembrane-Semaphorins: The Plexin Family

To date, nine plexins divided into four subfamilies (A-D) have been identified.58 Plexins are single-membrane-spanning protein of approximately 240 kDa that possess a sema domain near the N-terminal part, followed by cysteine-rich motifs, Met-related sequences (MRS)59 and glycine-proline-rich repeats (Fig. 2). The cytoplasmic part of plexins possesses a characteristic domain of 600 amino acids called the SP domain (Sex Plexins). This highly conserved domain within and across species contains some phosphorylation sites but is devoid of characteristic tyrosine kinase catalytic site.58 Similarly to neuropilins, plexins can form homodimers60 and heterodimers.61,62 In 2001, Takahashi and Strittmatter have proposed that Plexin-A1 semadomain binds to the remainder of the extracellular domain of the protein thereby inducing Plexin-A1 auto-inhibition.63 This auto-inhibition is released upon ligand binding to NRP1. An alternative view proposed by Turner et al60 suggests that plexin dimers could auto inhibit through reciprocal interactions of their PH1 and PH2 domains.

Plexins are considered to be the primary binding sites for semaphorins that do not bind to neuropilins. Hence, with the exception of Sema3E,64 class III semaphorins are unable to bind directly to plexins (see ref. 65 for review). Rather, plexin-neuropilin complexes are required as high-affinity receptors for secreted semaphorins, neuropilin acting as the ligand binding subunit while the plexin subunit ensures signal transduction.66 Several neuropilin/plexin couples have been identified to transduce the diverse biological effects of semaphorins.66-69 In any case, at least one plexin has been identified for each semaphorin class as the signaling partner. The exact nature of the domains controlling receptor complex formation and/or binding is not known. However, structural analysis and crystal structure characterization strongly support the crucial role of the sema domain contained both in semaphorins and plexins.70

Other Receptors Associated to Semaphorin Signaling

Mounting evidence is now consistent with a strong molecular diversity of the receptors and coreceptors of semaphorins. This section briefly reviews the different components which have been clearly showed to control semaphorin signaling or binding.

VEGFRs

Vascular Endothelial Growth Factor (VEGF) family is a major regulator of angiogenesis71 whose members bind to three tyrosine kinase receptors: VEGFR1, VEGFR2 and VEGFR3. Soker and collaborators discovered in 199872 that NRP1 is a fourth receptor for VEGF165 (a splice variant of the VEGF-A isoform), suggesting an interplay between VEGF and semaphorin signaling. Indeed, VEGF165 and Sema3A bind to NRP1 with the same affinity and compete for NRP1 binding. VEGF165 binds to NRP1 via interactions between the heparin binding domain of VEGF and the b1 domain of NRP1,55,73 which also interacts with the basic domain of semaphorins. Soker and collaborators also demonstrated that binding of VEGF165 to NRP1 enhances affinity of VEGF for VEGFR2 and that NRP1 expression potentiates VEGF165 chemotactic effect.72 Finally, NRP1 is also a receptor for other members of the VEGF family (VEGF-B and VEGF-E forms) and placental-growth factor-2 (PlGF-2). VEGF165 and PlGF-2, but also VEGF145 and VEGF-C bind to NRP2.74 Gu and collaborators suggested that the NRP1-enhanced affinity of VEGF165 for VEGFR-2 may reveal a receptor complex composed of the two proteins,55 but the domains required for the interaction between the two receptors have not been yet characterized. Nevertheless, NRP1 can bind VEGFR-1 with high affinity, and this interaction inhibits the binding of NRP1 to VEGF165. VEGFR-1 may then function as a negative regulator of angiogenesis by competing with NRP1.73 In contrast, repulsion by Sema3A depends on both NRP1 and VEGFR-1 in neural precursor cells.37 Thus, VEGFR-1 might serve as a co receptor for NRP1 in the transduction of Sema3A signaling. This is further supported by the Sema3A-dependent selective recruitment of MAP kinases by a receptor complex involving VEGFR-1 activation.75 Finally, it has been shown that Plexin-A1 can form a functional complex with VEGFR-2 in the cardiac tube.76 This complex has been reported to be involved in Sema6D signaling during cardiac morphogenesis.

L1-CAM and Nr-CAM

L1-CAM belongs to the immunoglobulin superfamily of adhesion molecules. This glycoprotein contains 6 immunoglobulin-like domains and 5 fibronectin-like domains. In addition to its classical cell adhesion function, L1 has now been implicated in Sema3A signaling. Indeed, L1-deficient axons do not respond to Sema3A. Coimmunoprecipitation and binding assays showed that L1 and NRP1, but not NRP2, interact with each other through their extracellular domains to form a stable complex. Moreover, soluble L1 converts Sema3A-induced axonal repulsion into attraction.77 Recently, Castellani and collaborators showed that upon binding to NRP1, L1 and NRP1 are cointernalized through a clathrin-dependent mechanism mediated by L1.78 Hence, this group has also demonstrated that NrCAM, a member of the immunoglobulin superfamily adhesion molecule of the L1 subfamily, associates with neuropilin-2 and is a component of a receptor complex for Sema3B and Sema3F.79

Heparin Binding Domains

A quantitative optical biosensor-based binding assay revealed that NRP1 interacts with a subset of heparin-binding proteins, notably fibroblast growth factor FGF-1, FGF-2, FGF-4, FGF-7, FGF receptor and hepatocyte growth factor/scatter factor (HGF/SF). These results suggest that NRP1 possesses a “heparin” mimetic site that is able to interact at least in part through ionic bonding with the heparin binding site of several proteins.80 The biological relevance of these interactions has to be characterized.

Integrins

Integrins are functional heterodimers composed of α and β subunits.81 There are 18 α and 8 β subunits that associate to form 24 integrin receptors with different ligand specificities.82 Pasterkamp and collaborators showed that Sema7A has a pronounced effect on axon outgrowth, and that this activity is dependent on β-subunit-containing integrin receptor but is plexin-independent.83 Several studies have also outlined the potential role of integrins in semaphorin signaling in other systems. Serini and collaborators for example showed that autocrine loops of class 3 chemorepellent semaphorins exert an essential permissive role in vasculature remodeling by inhibiting integrin-mediated adhesion of endothelial cells to the extracellular matrix, allowing the necessary de-adhesion for vascular remodeling.84 Finally, the poxvirus A39R, member of the semaphorin family, induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion.85

CD72, Tim2

CD72 is a 45-kDa type II transmembrane protein belonging to the C-type lectin family. Sema4D, the first semaphorin shown to be expressed in the immune system,86 specifically binds to CD72 on B cell surface when Plexin-B1 is not expressed.87,88 In that particular case, Sema4D may enhance B cells response by inhibiting the CD72 negative effect.

Tim 2 belongs to the Tim protein family characterized by expression on T cells and the presence of conserved immunoglobulin and mucin domains. Sema4A, expressed on dendritic cell surface, enhances T cells activation through binding to Tim 2.89 Given the crucial roles of Sema4A and Sema4D signaling during the immune response, these two signals make of class IV semaphorins as a new family of immunoregulatory molecules90 using specific receptors.

Scatter Factor Receptor

Recent evidence proposes that various tyrosine kinase receptors can be associated to the semaphorin receptor complex. Met and Ron tyrosine kinases can form disulfide-linked heterodimers and are members of the Scatter Factor receptor family containing a sema domain and a MRS sequence in their extracellular part. Giordano and collaborators showed that in cancer cells expressing the endogenous proteins, Plexin-B1 and Met associate in a complex to elicit invasive growth in response to Sema4D.91 The same group also demonstrated that Met and Ron receptors can specifically interact with each of the three members of class B plexins. Interestingly, the role of Met/Ron interaction with plexins could be the fine-tuning of the invasive growth program of tumor cells.92 Finally, Sema5A can trigger the intracellular signaling of Met via a receptor complex including Plexin-B3.93

Off-Track

Off-track (OTK) belongs to the neurotrophin receptor family. It is a glycoprotein of 160 kDa whose extracellular domain contains six immunoglobulin repeats.94 In Drosophila, OTK and class A plexins can associate as components of a receptor complex mediating the repulsive signal in response to Sema1a.95 Nevertheless, despite its homology with tyrosine kinase receptors, OTK itself is probably not an active tyrosine kinase and it should be determined if OTK recruits another protein for plexin phosphorylation. Moreover, Toyofuku and collaborators recently showed that Sema6D exerts expansion or narrowing of the ventricular chamber during cardiac morphogenesis through region-specific association of Plexin-A1 with off-track or VEGFR-2.76

Intracellular Signal Transduction

As described so far, the diversity of the semaphorin functions is related to the assembly of specific receptor complexes composed of various proteins. This diversity, not always demonstrated in neuronal cells, is the source of a wide range of possible intracellular pathways. Here, we decided to present the signaling cascades intimately linked to the signaling properties of the major transducer elements of the semaphorin receptor complex (Fig. 4).

Figure 4. Representative diagram of semaphorin intracellular pathways.

Figure 4

Representative diagram of semaphorin intracellular pathways.

Role of Rho GTPases

Consistent with the considerable amount of data collected on Sema3A, most of the described signaling pathways relate to this protein and its association to the neuropilin/plexin complex. As previously mentioned, NRP1 is not able to trigger any intracellular signal. Thus, the whole signaling cascade depends on the pathways recruited upon co receptors activation. Before the identification of plexins as the main signaling receptors of semaphorins, two studies by the groups of Strittmatter and Bamburg suggested the involvement of members of the Rho-GTPases family during Sema3A growth cone collapse.96,97 These studies revealed a complex and somehow controversial role of Rac1 by transfection into neurons of dominant negative form or constitutively active form of the protein. The mechanism of action has been recently elucidated by different studies showing that Rac1 is sequestered away from its effector PAK thereby favoring actin depolymerisation pathways.98-100 Subsequent studies also revealed the direct interaction of the cytoplamic tails of plexins with RhoGTPases. The group of Püschel for example determined that Plexin-A1 is able to bind to the small G proteins Rnd-1 and Rho-D.101 Interestingly, these two GTPases compete for binding to the same site thereby controlling Plexin-A1 activation or inactivation respectively. Moreover, Plexin B1-Rac interaction is able to modulate the binding of Sema4D to Plexin B1.102 Intriguingly, the Plexin-B1 possesses an intrinsic guanine triphosphate (GTP)ase activating protein activity for R-Ras, a member of Ras family of small GTPases. This particular activity has been shown to be required in promoting cell adhesion and neurite outgrowth through integrin activation.103 Several studies also demonstrated that Rho-specific GEFs (activators of Rho-GTPases) such as PDZ-Rho-GEF and LARG ensure coupling of RhoA to Plexin B.104-107 RhoA has been shown to mediate Sema4D-induced growth cone collapse of hippocampal neurons.108 Finally, (PDZ)-RhoGEF and LARG can also bind to Plexin-B2 and Plexin-B3.107 As expected from the classical description of the interplay between Rho-GTPases,109 a concomitant inactivation of Rac1 and activation of RhoA is necessary to trigger growth cone collapse. Although differences exist between RhoGTPases/plexin interactions in vertebrates and invertebrates, the emerging scheme is the existence of a functional balance between Rho-GTPases that controls axon growth or inhibition in response to semaphorins. Ultimately, such a balance leads the modulation of actin cytoskeleton reorganization (see Nothias chapter).

The Role of Cytoskeleton Dynamics Regulators

The actin cytoskeleton is precisely regulated by multiple factors that are very similar in all cell types. Like in other cells, the Rho-GEFs and Rho-GAPs are the upstream regulators which control activation or inhibition of Rho-GTPases in neurons. Actin dynamic is thus regulated by Rho-GTPases at the level of filament nucleation and branching (role of ARP2/3 complex), filament extension (role of capping proteins) and actin recycling (role of cofilin).110,111 It has been shown that Sema3A-induced growth cone collapse of mouse DRG neurons is correlated with a rapid increase of the phosphorylation state of cofilin, an actin binding protein supporting depolymerisation when phosphorylated.112 This phosphorylation of cofilin is triggered by the Ser/Thr kinase LIM-kinase. Many additional kinases have been identified in the semaphorin signaling cascade.

Among them, the Fes/Fps tyrosine kinase has been implicated in Sema3A-induced growth cone collapse.113 Fes/Fps is a nonreceptor-type tyrosine kinase shown to directly bind to the cytoplasmic region of Plexin-A1. Strikingly, the binding of Fes/Fps to Plexin-A1 is prevented by the association of NRP1 to Plexin-A1. The Fes/Fps tyrosine kinase also phosphorylates the CRMP2 (Collapsin Response Mediator Protein 2)/CRAM (CRMP-associated-molecules) complex.113 This complex was originally identified as a crucial element of the Sema3A intracellular signaling during growth cone collapse.114,115 In addition to Fes/Fps, the Fyn tyrosine kinase associates with and phosphorylates Plexin-A2 in response to Sema3A.116 Furthermore, Fyn can phosphorylate the serine/threonine kinase Cdk5 which in turn can phosphorylate CRMP2.117

Another Ser/Thr kinase, GSK3 β, is also able to phosphorylate CRMP2. Interestingly, the phosphorylation of CRMP2 by both Cdk5 and GSK3β is essential for Sema3A-induced growth cone collapse.118,119 CRMP2 binds to tubulin heterodimers and is supposed to control microtubules assembly.120 Hence, Cdk5 and GSK3β may ensure the regulation of microtubules dynamics by phosphorylation of CRMP2 in response to semaphorins.

The continuing identification of novel intracellular molecular partners of plexins is demonstrated by the recent implication of MICAL, a flavoprotein oxidoreductase that binds to the C2 domain of Plexin-A in Drosophila to ensure Sema1a/Plexin-A-mediated repulsive axon guidance.121 Hence, it has been shown that Sema3A stimulates the synthesis of 12(S)-hydroxyeicosatetraenoic acid (HETE) to induce DRG growth cone collapse.122

The Role of the MAP Kinase Pathway

The MAP kinases ERK1/2 and p38 are important signaling components often associated to cell proliferation, cell migration or cell death. Indeed, the MAP kinase pathway has been shown to regulate signaling of guidance molecules of the Netrin or Ephrin families.123- 126 As expected, the MAP kinase pathway is also recruited by semaphorins. This has been demonstrated by the activation of ERK1/2 during Sema3A-induced retinal growth cone collapse.127 Moreover, the neurotrophic effect of Sema4D in PC12 cells also requires ERK1/2 activation.128 The recruitment of MAP kinases during semaphorin signaling is receptor dependent. As shown by Pasterkamp and collaborators,83 the Sema7A growth promoting effect requires an integrin-dependent MAP kinase signaling. Moreover, our work demonstrated the selective recruitment of ERK1/2 during Sema3A/VEGFR-1-mediated neural precursor cells repulsion and p38 activation to trigger cell death.75 The integrity of the MAP kinase cascade has been shown to be important to ensure outgrowth promoting effect of L1 and other adhesion molecules such as NCAM.129 It would therefore not be surprising that L1-mediated semaphorin effects also require activation of MAP kinases. Many arguments including the involvement of MAP kinases in the signaling of VEGF,130 the activation of MAP kinases by small GTPases131 and the multiplicity of the semaphorin receptors linked to MAP kinases strongly support this pathway as a point of convergence in semaphorin signaling. Hence the complexity of the interactions between intracellular pathways is illustrated by the ability of Sema3F to suppress NGF-dependent activation of the PI3K/Akt and ERK1/2 pathways,132 two pathways involved in cancer cells to trigger EGF-induced NRP1 expression.133

Conclusion

Extensive work has been conducted over the past decade to elucidate the biological functions of semaphorins. A particular effort has been done to understand the complex signaling pathways recruited by semaphorins to exert their various roles. While the inhibitory pathways have been well dissected, semaphorin-triggered growth promoting pathways remain obscure. Nevertheless, compelling data being fully detailed in the chapter by Holt and collaborators (see Holt chapter, this book) identified cGMP as a key regulator of semaphorin function.134,135 Future studies will have to investigate this fascinating question making things much more complex since inhibition and growth promotion can take place in the same cell in the presence of a single semaphorin.19 Moreover, the driving force of guidance cues is intimately linked to the existence of gradients.136 In the case of class 3 semaphorins, we have shown that growth cones have stereotyped responses to semaphorin gradients and do not require precise dimensioned gradients to be attracted or repulsed.137 The exact molecular mechanism allowing growth cones to read and integrate semaphorin gradients remain obscure. Hence, the molecular hierarchy of the signaling pathways will have to be determined when cells are exposed to semaphorin combinations and, to address the biological reality, when neuronal growth cones are exposed to multiple families of guidance cues that may have converging or diverging signaling pathways.

Acknowledgment

The lab of DB is supported by grants from the FRM (#INE20011109006), BQR-ULP (#BE/CH/2001-225V) and ACI JC (#5327) and APETREIMC. BG is supported by Neurex. We thank AW Püschelschel for critical reading of the manuscript.

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