Semaphorins are a class of secreted and membrane proteins that were originally identified as axonalgrowth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes.[1][2] Semaphorins are usually cues to deflect axons from inappropriate regions, especially important in the neural system development. The major class of proteins that act as their receptors are called plexins, with neuropilins as their co-receptors in many cases. The main receptors for semaphorins are plexins, which have established roles in regulating Rho-family GTPases. Recent work shows that plexins can also influence R-Ras, which, in turn, can regulate integrins. Such regulation is probably a common feature of semaphorin signalling and contributes substantially to our understanding of semaphorin biology.
Every semaphorin is characterised by the expression of a specific region of about 500 amino acids called the sema domain.
Semaphorins were named after the English word Semaphore, which originated from Greek, meaning sign-bearer.[3]
Classes
The Semaphorins are grouped into eight major classes based on structure and phylogenetic tree analyses.[4] The first seven are ordered by number, from class 1 to class 7. The eighth group is class V, where V stands for virus. Classes 1 and 2 are found in invertebrates only, whilst classes 3, 4, 6, and 7 are found in vertebrates only. Class 5 is found in both vertebrates and invertebrates, and class V is specific to viruses.
Classes 1 and 6 are considered to be homologues of each other; they are each membrane bound in invertebrates and vertebrates, respectively. The same applies to classes 2 and 3; they are both secreted proteins specific to their respective taxa.
Each class of Semaphorin has many subgroups of different molecules that share similar characteristics. For example, Class 3 Semaphorins range from SEMA3A to SEMA3G.
Different semaphorins use different types of receptors:
Most Semaphorins use receptors in the group of proteins known as plexins.
Class 3 semaphorins signal through heterocomplexes of neuropilins, Class A Plexins, and cell adhesion molecules, and the makeup of these complexes likely provides specificity for binding and transducing signals from different Class 3 Semaphorins.[5]
Class 7 Semaphorin are thought to use integrins as their receptors.
Semaphorins are very versatile. Their discovery was in regards to axon guidance in the limb buds of grasshoppers in 1992, but since then, it has been discovered that semaphorins have a role in many processes. They not only guide axons in development, but also have major roles in immune function (classes 4, 6, and 7) and the development of bones. Class 3 semaphorins are one of the most versatile semaphorin classes, in which Sema3a is the most studied.
During development, semaphorins and their receptors may be involved in the sorting of pools of motor neurons and the modulation of pathfinding for afferent and efferent axons from and to these pools.[6] For instance, Sema3a repels axons from the dorsal root ganglia, facial nerves, vagal nerves, olfactory-sensory, cortical nerves, hippocampal nerves and cerebellar nerves.
Class 3 semaphorins have an important function after traumatic central nervous system injuries, such as spinal cord injury. They regulate neuronal and non-neuronal cells associated with the traumatic injury due to their presence in the scar tissue. Class 3 semaphorins modulate axonal regrowth, re-vascularisation, re-myelination and the immune response after central nervous system trauma.[7]
↑ Cohen S, Funkelstein L, Livet J, Rougon G, Henderson CE, Castellani V, Mann F (April 2005). "A semaphorin code defines subpopulations of spinal motor neurons during mouse development". The European Journal of Neuroscience. 21 (7): 1767–76. doi:10.1111/j.1460-9568.2005.04021.x. PMID15869472. S2CID24049774.
An axon, or nerve fiber, is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.
In neuroanatomy, the optic chiasm, or optic chiasma, is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrates, although in cyclostomes, it is located within the brain.
A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.
Neuropilin is a protein receptor active in neurons.
Synaptic pruning, a phase in the development of the nervous system, is the process of synapse elimination that occurs between early childhood and the onset of puberty in many mammals, including humans. Pruning starts near the time of birth and continues into the late-20s. During pruning, both the axon and dendrite decay and die off. It was traditionally considered to be complete by the time of sexual maturation, but this was discounted by MRI studies.
VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.
Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.
A plexin is a protein which acts as a receptor for semaphorin family signaling proteins. It is classically known for its expression on the surface of axon growth cones and involvement in signal transduction to steer axon growth away from the source of semaphorin. Plexin also has implications in development of other body systems by activating GTPase enzymes to induce a number of intracellular biochemical changes leading to a variety of downstream effects.
Neuropilin 2 (NRP2) is a protein that in humans is encoded by the NRP2 gene.
Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.
Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.
Semaphorin-4D (SEMA4D) also known as Cluster of Differentiation 100 (CD100), is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.
Semaphorin-3F is a protein that in humans is encoded by the SEMA3F gene.
Semaphorin-3C is a protein that in humans is encoded by the SEMA3C gene.
Semaphorin 7A, GPI membrane anchor (SEMA7A) also known as CD108, is a human gene.
Plexin-A4 is a protein that in humans is encoded by the PLXNA4 gene.
The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.
Semaphorin 3E is a protein that in humans is encoded by the SEMA3E gene.
Alain Chédotal is a French researcher specialising in the development of neural circuits. He has been a member of the French Academy of sciences since 2017.
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