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Semaphorins are a class of secreted and membrane proteins that act as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. They are usually cues to deflect axons from inappropriate regions, especially important in neural system development. The major class of proteins that act as their receptors are called plexins.

Every Semaphorin is characterised by the expression of a specific region of about 500 amino acids called the Sema domain.


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. 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:

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.

Each Class of Semaphorin has many subgroups of different molecules that share similar characeristics. 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 Neuropilins as co-receptors with Plexins
  • Class 7 Semaphorins 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 hand in many proverbial doors. They not only guide axons in development, but also have major roles in immune function (Classes 4 and 7) and the development of bones. One of the most versatile semaphorin classes is the Sema-3 class, and specifically Sema-3A.

Sema-3A is responsible for repelling axons from the dorsal root ganglia, facial nerves, vagal nerves, olfactory-sensory, cortical nerves, hippocampal nerves, cerebellar, etc.

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