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  • Review Article
  • Published:

Getting neural circuits into shape with semaphorins

Nature Reviews Neuroscience volume 13, pages 605–618 (2012)Cite this article

Subjects

Key Points

  • The semaphorins are a family of membrane-associated and secreted proteins that mediate diverse aspects of neural circuit development, ranging from neuron migration to repulsive axon guidance and synapse formation. In neurons, semaphorins signal predominantly through receptor proteins of the plexin and neuropilin families.

  • The presentation and function of semaphorin receptors is under tight molecular control to spatiotemporally regulate the responsiveness of growth cones to semaphorins and to diversify their effects, thereby allowing semaphorins to mediate a disproportionately large number of wiring decisions.

  • Neurons can expand their semaphorin signalling capacities by regulating the subunit composition of their receptors (thus allowing semaphorins to act as neurite attractants and repellents), and by utilizing semaphorins as ligands or receptors. Expression of semaphorin receptors is controlled at multiple different levels, including at the transcriptional and post-transcriptional levels.

  • Although originally identified as growth cone-collapsing factors, semaphorins mediate a plethora of functions beyond axon pathfinding in the developing and mature nervous system. For example, during early development SEMA3A facilitates dendrite formation and inhibits axon specification through the activation of different cyclic GMP-dependent signalling pathways. Moreover, once neurons have been formed, secreted semaphorins (SEMA3s) and transmembrane semaphorins (SEMA5 and SEMA6) help to restrict neuronal processes to their targets in a topographical or lamina-specific manner.

  • Upon arrival in their synaptic target fields, axons must identify their postsynaptic partners and generate synaptic contacts, often at specific cellular domains of the postsynaptic cell. Recent work in different parts of the nervous system suggests that these processes are controlled by semaphorins.

  • Emerging evidence suggests that uncontrolled semaphorin expression and function has an important role in nervous system-related diseases and regeneration failure. Therefore, understanding the mechanistic details of semaphorin signalling and function will be crucial in the design of strategies to modulate neural injury and disease.

Abstract

Semaphorins are key players in the control of neural circuit development. Recent studies have uncovered several exciting and novel aspects of neuronal semaphorin signalling in various cellular processes — including neuronal polarization, topographical mapping and axon sorting — that are crucial for the assembly of functional neuronal connections. This progress is important for further understanding the many neuronal and non-neuronal functions of semaphorins and for gaining insight into their emerging roles in the perturbed neural connectivity that is observed in some diseases. This Review discusses recent advances in semaphorin research, focusing on novel aspects of neuronal semaphorin receptor regulation and previously unexplored cellular functions of semaphorins in the nervous system.

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Figure 1: Semaphorins and their neuronal receptor complexes.
Figure 2: Novel role for SEMA3A in dendrite specification.
Figure 3: Axon-derived SEMA3s in olfactory topographical map formation.
Figure 4: Transmembrane semaphorins control laminar neurite stratification in the retina.
Figure 5: SEMA3s determine synaptic specificity at the cellular and subcellular levels.

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Acknowledgements

The author thanks A. L. Kolodkin, A. Kumanogoh and C. Siebold for valuable discussions and their critical comments on the manuscript. He also apologizes to all the investigators whose research could not be appropriately cited in the manuscript owing to space limitations.

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  1. Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands

    R. Jeroen Pasterkamp

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Glossary

Growth cone

The motile tip of growing neurites that senses molecular cues in the extracellular environment.

GTPase-activating proteins

(GAPs). A family of proteins that bind and inactivate small GTP-binding proteins by increasing their rate of GTP hydrolysis.

RE1-silencing transcription factor

(REST). A member of the Kruppel-type zinc finger transcription factor family that represses gene transcription by binding the neuron-restrictive silencer element in DNA (NRSE or RE1).

Mossy fibres

In the hippocampus, mossy fibres are unmyelinated axons that project from granule cells in the dentate gyrus to pyramidal neurons in the CA3 region.

Stratum lucidum

A thin layer in the CA3 region just inwards of the stratum pyramidale (the layer containing pyramidal neurons) that contains mossy fibre axons and the proximal dendrites of CA3 pyramidal neurons.

Maxillary palps

A pair of olfactory organs in Drosophila melanogaster, and other insects, that arise from the proboscis and contain a small number of olfactory sensory neurons.

Antennal lobe

An olfactory structure in Drosophila melanogaster, and other insects, that is composed of glomeruli in which the axons of olfactory sensory neurons synapse with their postsynaptic target neurons.

Bipolar cells

Bipolar cells synapse with either rods or cones, and also receive inputs from horizontal cells. They directly or indirectly (through amacrine cells) transmit this information onto ganglion cells.

Amacrine cells

A class of interneurons that are synaptically active in the inner plexiform layer and influence retinal signal processing at the level of contact between bipolar and ganglion cells.

Horizontal cells

Horizontal cells are laterally interconnecting neurons in the outer plexiform layer of the retina. They integrate and regulate the input from multiple photoreceptor cells.

Triceps muscle

A large muscle on the back of the upper limb or forelimb of many vertebrates. It is responsible for extension of the elbow joint (and hence straightening of the limb).

Cutaneous maximus muscle

A thin subcutaneous muscle that covers the trunk and flexes the skin.

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Pasterkamp, R. Getting neural circuits into shape with semaphorins. Nat Rev Neurosci 13, 605–618 (2012). https://doi.org/10.1038/nrn3302

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