Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene. [5] [6] [7]
Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene. [5] [6] [7]
The SEMA3A gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted Semaphorin-3A protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. [7]
Semaphorin-3A is secreted by neurons and surrounding tissue to guide migrating cells and axons in the developing nervous system. Axon pathfinding is the process by which neurons follow very precise paths, sends out axons, and react to specific chemical environments to reach the correct endpoint. The guidance is critical for the precise formation of neurons and the surrounding vasculature. Guidance cues, such as Sema3A, induce the collapse and paralysis of neuronal growth cones during development of the nervous system.
This guidance cue for axons of neurons is signaled through receptor complexes containing Neuropilin-1 (NRP1) and a co-receptor. [8] [9] [10] One of the first identified intracellular messenger required for the growth cone-collapse induced by Sema3A is the CRMP protein called CRMP2.
In addition to its role in the nervous system, Sema3A also acts as an inhibitor of angiogenesis, the process by which new blood vessels develop. [11]
The protein semaphorin-3A is highly expressed in scar tissue after traumatic central nervous system injuries, such as spinal cord injury. Semaphorin-3A, and the other class 3 semaphorins, contributes to the failure of neuronal regeneration after CNS injury by regulating axonal re-growth, re-myelination, re-vascularisation, and the immune response. [12]
Increased expression of semaphorin-3A is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [7] [13]
Additionally, the terminal Schwann cells of amyotrophic lateral sclerosis (ALS) mice (SOD1 mutant) express semaphorin-3A at fast-fatigable fiber neuromuscular junctions greater than wild-type mice. [14] This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms. [15] Because semaphorin-3A is involved in growth cone collapse, axon pruning, and repulsion, it potentially holds a causal relationship to synaptic weakening and denervation that precedes motor neuron apoptosis in ALS. [14]
Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. 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.
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.
Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative 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.
The Sema domain is a structural domain of semaphorins, which are a large family of secreted and transmembrane proteins, some of which function as repellent signals during axon guidance. Sema domains also occur in the hepatocyte growth factor receptor, Plexin-A3 and in viral proteins.
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-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.
Plexin B1 is a protein of the plexin family that in humans is encoded by the PLXNB1 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.
Plexin-A1 is a protein that in humans is encoded by the PLXNA1 gene.
Semaphorin 7A, GPI membrane anchor (SEMA7A) also known as CD108, is a human gene.
Plexin-A2 is a protein that in humans is coded by the PLXNA2 gene.
Plexin-A4 is a protein that in humans is encoded by the PLXNA4 gene.
Collapsin response mediator protein family or CRMP family consists of five intracellular phosphoproteins of similar molecular size and high (50–70%) amino acid sequence identity. CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules. Cleaved forms of CRMPs have also been linked to neuron degeneration after trauma induced injury.
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.
PDB gallery | |
|---|---|
|
