Semaphorins are a class of secreted and membrane protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s that act as axonal growth cone
Growth cone
A growth cone is a dynamic, actin-supported extension of a developing axon seeking its synaptic target. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope...

 guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

 complexes. They are usually cues to deflect axons from inappropriate regions, especially important in neural system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...

 development. The major class of proteins that act as their receptors are called plexin
A plexin is a protein which acts as a receptor for semaphorin.Genes include:* PLXNA1, PLXNA2, PLXNA3, PLXNA4A, * PLXNB1, PLXNB2, PLXNB3* PLXND1...


Every semaphorin is characterised by the expression of a specific region of about 500 amino acids called the sema domain
Sema domain
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 and and in viral proteins.CD100 is...



There are 8 major classes of semaphorins. The first 7 are ordered by number, from class 1 to class 7. The eighth group is class V, where V stands for virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

. 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.

In humans, the genes are:
  • SEMA3A
    Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type domain, a PSI domain and a Sema domain...

    , SEMA3B
    Semaphorin-3B is a protein that in humans is encoded by the SEMA3B gene.-Further reading:...

    , SEMA3C
    Semaphorin-3C is a protein that in humans is encoded by the SEMA3C gene.-Further reading:...

    , , , SEMA3F
    Semaphorin-3F is a protein that in humans is encoded by the SEMA3F gene.-Further reading:...

  • SEMA4A
    Semaphorin-4A is a protein that in humans is encoded by the SEMA4A gene.-Further reading:...

    , SEMA4B
    Semaphorin-4B is a protein that in humans is encoded by the SEMA4B gene.-Further reading:...

    , SEMA4C
    Semaphorin-4C is a protein that in humans is encoded by the SEMA4C gene.-Further reading:...

     ("SEMAF"), SEMA4D
    Semaphorin-4D also known as Cluster of Differentiation 100 , is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.- Function :...

    , , SEMA4F
    Semaphorin-4F is a protein that in humans is encoded by the SEMA4F gene.-Further reading:...

    , SEMA4G
    Semaphorin-4G is a protein that in humans is encoded by the SEMA4G gene.-Further reading:...

  • SEMA5A
    Semaphorin-5A is a protein that in humans is encoded by the SEMA5A gene.Semaphorine 5A also plays a role in autism, reducing the ability of neurons to form connections with other neurons in certain brain regions.-Further reading:...

  • SEMA6A
    Semaphorin-6A is a protein that in humans is encoded by the SEMA6A gene.In melanocytic cells SEMA6A gene expression may be regulated by MITF.-Further reading:...

    , , SEMA6C
    Semaphorin-6C is a protein that in humans is encoded by the SEMA6C gene.-Further reading:...

  • SEMA7A
    Semaphorin 7A, GPI membrane anchor also known as CD108 , is a human gene....

Classes 1 and 6 are considered to be homologues of each other, since they are both membrane bound in vertebrates and invertebrates. The same applies to classes 2 and 3, because they are both secreted proteins specific to phylum
In biology, a phylum The term was coined by Georges Cuvier from Greek φῦλον phylon, "race, stock," related to φυλή phyle, "tribe, clan." is a taxonomic rank below kingdom and above class. "Phylum" is equivalent to the botanical term division....


Each class of semaphorin has many subgroups of different molecules that share similar characteristics. For example, semaphorin class 3 ranges from Sema-3A to Sema-3E. Each one of the class 3 semaphorins are expressed in different regions of the body during development and whilst some encourage the growth of axons, others inhibit it.

Semaphorin receptors

Different semaphorins use different types of receptors:
  • Most semaphorins use receptors in the group of proteins known as plexins.
  • Class 3 semaphorins utilise a group of proteins known as neuropilin
    Neuropilin is a protein receptor active in neurons.There are two forms of Neuropilins, NRP-1 and NRP-2. They are transmembrane glycoproteins, and predominantly co-receptors for another class of proteins known as semaphorins...

    s as co-receptors with plexins
  • Class 7 semaphorins are thought to use integrins as their receptors.

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.


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. One of the most versatile semaphorin classes is number 3, and specifically Sema-3A.

Sema-3A repels axons from the dorsal root ganglia, facial nerves, vagal nerves, olfactory-sensory, cortical nerves, hippocampal nerves and cerebellar nerves.
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