Semaphorin-3A is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''SEMA3A''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
The ''SEMA3A'' gene is a member of the
semaphorin
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 (biochemistry), recepto ...
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
dendrite
A dendrite (from Ancient Greek language, Greek δένδρον ''déndron'', "tree") or dendron is a branched cytoplasmic process that extends from a nerve cell that propagates the neurotransmission, electrochemical stimulation received from oth ...
s. In both cases, the protein is vital for normal neuronal pattern development.
Semaphorin-3A is secreted by neurons and surrounding tissue to guide migrating cells and
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
s in the developing nervous system. Axon pathfinding is the process by which neurons follow very precise paths, send 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 the development of the nervous system.
This guidance cue for
axon
An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see American and British English spelling differences#-re, -er, spelling differences) is a long, slender cellular extensions, projection of a nerve cell, or neuron, ...
s of
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s is signaled through receptor complexes containing Neuropilin-1 (
NRP1) and a co-receptor.
One of the first identified intracellular messengers required for the
growth cone
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago ...
-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.
Clinical significance
The protein semaphorin-3A is highly expressed in scar tissue after traumatic central nervous system injuries, such as
spinal cord injury
A spinal cord injury (SCI) is damage to the spinal cord that causes temporary or permanent changes in its function. It is a destructive neurological and pathological state that causes major motor, sensory and autonomic dysfunctions.
Symptoms of ...
. Semaphorin-3A, and the other class 3
semaphorin
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 (biochemistry), recepto ...
s, contribute to the failure of
neuronal regeneration after CNS injury by regulating axonal re-growth,
re-myelination,
re-vascularisation, and the
immune response
An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
.
Increased expression of semaphorin-3A is associated with
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
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
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
.
Additionally, the
terminal Schwann cells of
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...
(ALS) mice (
SOD1 mutant) express semaphorin-3A at
fast-fatigable fiber neuromuscular junctions
A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber.
It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.
Muscles require innervation to ...
greater than
wild-type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
mice.
This expression is greatest pre-symptomatically corresponding to ALS progression in which fast-fatigable fiber denervation precedes clinical symptoms.
Because semaphorin-3A is involved in
growth cone
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago ...
collapse,
axon pruning, and repulsion, it potentially holds a causal relationship to
synaptic weakening and denervation that precedes
motor neuron
A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
in ALS.
References
Further reading
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External links
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{{PDB Gallery, geneid=10371