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Alternative splicing controls teneurin-3 compact dimer formation for neuronal recognition


The establishment of neural connectivity is controlled by the interaction of cell surface molecules, present on the pre- and postsynaptic sides. Alternative splicing provides additional specificity through the creation of different cell adhesion molecule isoforms.

In an international collaboration between the Hindges and Drescher labs and colleagues from the Netherlands, Christos Gogou et al. investigated the structural and functional consequences of generating different splice variants for teneurin-3. Teneurin-3 is a member of the teneurin family of cell adhesion molecules which plays a prominent role in circuit wiring across various species and is linked to a variety of disorders. Using Cryo-EM, small-angle X-ray scattering and negative stain EM approaches, the study shows that splice variants at two different sites in the protein generate compact structures at the membrane, however, with distinct overall conformations to allow various cis- and trans-dimer arrangements. Cell adhesion and in vitro stripe assays confirmed functionally that these protein isoforms exhibit clear differences regarding homophilic interactions and the control of axon outgrowth, as predicted by the structural data.

Gogou et al. provide a model where relatively short splice inserts of only ∼7 amino acids result in large structural rearrangements, hereby impacting trans-cellular interactions and neural circuit wiring.

By Robert Hindges