The semaphorins are an evolutionary conserved family of intercellular signalling proteins known to deliver guidance cues to growing axons and migrating cells during development. Semaphorins bind with high affinity to several distinct receptor families on the cell surface, including the neuropilins and plexins. The interaction of semaphorins and their receptor complexes triggers elaborate intracellular signalling pathways that in many cases regulate the cytoskeleton to control growth cone or cellular morphology. However, semaphorins also regulate cellular processes not directly related to changes in cytoskeletal dynamics such as apoptosis or cytokine release. Defects in semaphorin function have been associated with a variety of human diseases including amyotrophic lateral sclerosis, spinal cord injury and cancer, and studies have been initiated to use semaphorin proteins as therapeutic targets in human disorders.

Key Concepts:

  • Semaphorins are bi‐functional guidance cues mediating attractive and repulsive chemotactic responses.

  • Semaphorin receptor complexes are composed of ligand binding, signal‐transducing and modulatory subunits.

  • Context‐dependent changes in receptor or signalling components determine the downstream effect of semaphorins.

  • Semaphorins can act as ligands and receptors, a process called bi‐directional signalling.

  • Secreted and membrane‐associated semaphorins regulate various aspects of neural circuit development.

  • Signalling cues that function downstream of semaphorin receptors includes protein kinases and small GTPases.

  • Semaphorins have been implicated in various human diseases and may serve as therapeutic targets.

Keywords: axon guidance; nervous system; neuronal growth cone collapse; neuropilin; plexin

Figure 1.

(a) Semaphorins and (b) their receptors. (a) Semaphorins exist as secreted, GPI‐anchored or membrane‐spanning proteins. Subclasses 1 and 2 represent invertebrate semaphorins, subclasses 3–7 vertebrate semaphorins and subclass V viral semaphorins. (b) Neuropilins, plexins, Off‐track (OTK), L1, Met, CD72, Tim‐2, and β1 subunit‐containing integrins serve as semaphorin receptors or components thereof. Domains: α, alpha subunit; α‐helic, α‐helical coiled‐coiled; β, beta subunit; BD, basic; C1, intracellular 1; C2, intracellular 2; C‐lec, C‐type lectin; CUB, complement binding; Cyto, cytoplasmic; Ext, extracellular; FIII, fibronectin type III; FV/FVIII, coagulation factor; G–P, glycine–proline‐rich; GPI, glycosylphosphatidylinositol anchor; Ig, immunoglobulin‐like; IgV, immunoglobin variable region; ITIM, immunoreceptor tyrosine‐based inhibitory motif; MAM, ‘Meprin, A5, Mu’; MRS, Met‐related sequence; Muc, mucine; PMR, polymorphic region; Sema, semaphorin; SS, signal sequence; TK, tyrosine kinase; and TR, thrombospondin.

Figure 2.

Semaphorins in invertebrate axon guidance. Semaphorins regulate axon fasciculation and the polarity of neurite growth in the grasshopper and fly nervous systems. (a) Ti pioneer axons project along a highly stereotyped pathway across the grasshopper limb bud to reach the CNS. In the developing limb Sema‐1a is expressed by a stripe of epithelial cells and Sema‐2a is distributed in a distal‐to‐proximal gradient. (b) Antibody perturbation of Sema‐1a results in severe defasciculation of ventral Ti projections. (c) Neutralising antibodies against Sema‐2a cause aberrant Ti projections throughout the developing limb. These results indicate that both the fasciculated state and polarity of Ti axon outgrowth depends on semaphorin function. (d) In the intact fly nervous system, motor axons express Sema‐1a and its receptor plexinA as they project through the ISN and ISNb nerves towards a specific subset of ventral muscles. (e) Ectopic expression of Sema‐1a in all ventral muscles prevents motor axons from defasciculating into the ventral muscle field. (f) In the absence of Sema‐1a, axons fail to defasciculate at specific choice points and therefore to extend towards the ventral muscles. Thus, axon‐derived Sema‐1a enables motor fibres to break off from the ISNb and to explore their target field. CNS, central nervous system; ISN, intersegmental nerve; PNS, peripheral nervous system; and Ti, Tibial pioneer neuron.

Figure 3.

Semaphorins in vertebrate axon guidance. The analysis of Sema3A−/−, neuropilin‐1−/− and neuropilin‐2−/− mutant mice has revealed a contribution of class 3 semaphorins to several axon guidance events during vertebrate development. (a and b) In the mouse peripheral nervous system Sema3A confines spinal nerve afferents to specific regions of the developing limbs. In both Sema3A−/− and neuropilin‐1−/− mutant mice these spinal projections are highly defasciculated and many axons overshoot their normal target fields. (c and d) In the developing mouse cortex, Sema3A is expressed in an apical‐to‐ventricular gradient, attracting dendrites to the pial surface and repelling axons towards the ventricular zone. In the absence of Sema3A both cortical dendrites and axons are severely misorientated.



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Further Reading

Ahmed A and Eickholt BJ (2007) Intracellular kinases in semaphorin signaling. Advances in Experimental Medicine and Biology 600: 24–37.

Kumanogoh A and Kikutani H (2010) Semaphorins and their receptors: novel features of neural guidance molecules. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 86: 611–620.

Pasterkamp RJ and Verhaagen J (2006) Semaphorins in axon regeneration: developmental guidance molecules gone wrong? Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 361: 1499–1511.

Schmidt ER, Pasterkamp RJ and van den Berg LH (2009) Axon guidance proteins: novel therapeutic targets for ALS? Progress in Neurobiology 88: 286–301.

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Serini G, Maione F, Giraudo E and Bussolino F (2009) Semaphorins and tumor angiogenesis. Angiogenesis 12: 187–193.

Yazdani U and Terman JR (2006) The semaphorins. Genome Biology 7: 211.

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van Erp, Susan, and Jeroen Pasterkamp, R(Dec 2011) Semaphorins. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000829.pub3]