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

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Neuronal network formation relies on cell adhesion molecules.
• Alternative splicing of these molecules adds specificity to neuronal connections.

Purpose of the Study:

• To elucidate the structural basis of teneurin-3 alternative splicing.
• To understand how splice variants influence teneurin interactions and neuronal wiring.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of teneurin-3 isoforms.
• Small-angle X-ray scattering (SAXS) and negative stain EM for structural analysis.
• Cell clustering and stripe assays to assess trans-cellular interactions.

Main Results:

• Identified compact dimeric ectodomain structures for teneurin-3 isoforms.
• Demonstrated that an EGF8-ABD contact stabilizes the dimer.
• Revealed variant-specific dimeric arrangements influencing trans-cellular interactions.
• Showcased how alternative splicing alters subunit arrangements in teneurin dimers.

Conclusions:

• Alternative splicing of teneurin-3 leads to rearrangements in dimeric subunit organization.
• These structural changes provide a basis for specific teneurin homo- and heterophilic interactions.
• Findings offer insights into how teneurins contribute to neuronal recognition and circuit wiring.