Network Brain

Alternative splicing provides us with the network BRAIN

In tissues with high complexity and functionality - like the brain - there is a demand for a very large number of proteins to perform the required functions. To provide this, neurons, and more specifically the synapses at the connecting points of neurons, have to be extraordinary variable. Therefore it is not surprising that alternative splicing occurs very frequently in brain tissues.

Synapses, the connectors in the brain

A complex and widely ramified network of neurons is necessary to ensure flow of information in the network brain. This occurs via synapses in the form of neurotransmitters. Neurotransmitters are chemicals that relay, amplify and modulate signals between a neuron and another cell. The synapse contains a small gap separating two neurons from each other.

"Brain proteins" - Neurexins and their ligands neurolingin

One family of proteins which are exclusively found in the brain is neurexins. These proteins play an important role in the formation of synapses. Neurexins can potentially bind to neurolingin. Neurolingin is a neuronal cell surface protein; the interaction of both proteins is required for the cells to attach to each other.

Both neurexins and neurolingins exist in numerous forms that are derived from multiple genes and alternative splicing. As a consequence of the alternative splicing process, different versions of proteins are produced, each of them resulting in the formation of synapses with different qualities.

Neurexins: Thousands of protein products made out of three genes

Three genes are responsible for the production of thousands of neurexins. Firstly, the three genes produce six principal neurexins where each gene makes two versions of neurexins:

•   α-neurexin mRNA (longer version)
•   β-neurexin mRNA (shorter version).

Neurexins are membrane proteins and the part of the protein that embeds into the membrane is nearly identical in all six proteins. However, the part of the protein which is on the surface of the cell is highly variable. This is achieved by the six primary neurexin mRNA transcripts being extensively alternatively spliced. They can potentially occur in thousands of different functionally important versions. Some of the different alternative splicing patterns occur in different classes of neurons, leading to different types of synapses.

The larger α-neurexin could potentially bind many ligands, the smaller β-neurexin could interact with a more limited number of molecules. However, the number of potential interactions is raised due to multiple alternative splicing events.

Several diseases have been associated with a dysfunction in neurolingin family members. Disruption of the connectivity between synapses or their activity has been implicated in abnormalities associated with neurodevelopmental disorders. Examples for such disorders are Fragile X mental retardation, Asperger Syndrome and Autism disorder.