Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration

Berbeira-Santana, M.; Peregrina, C.; Okuda, K.; Zhou, J. C.; Carrasquero-Ordaz, M.; Roberts, A. V.; Thomas, A. E.; Haanappel, E.; Chavent, M.; el Omari, K.; Baker, L. A.; Pederick, D.; Pardon, E.; Steyaert, J.; Naegerl, U. V.; del Toro, D.; Seiradake, E.

doi:10.1101/2025.09.09.671438

bioRxiv · 10.1101/2025.09.09.671438

Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration

Berbeira-Santana, M.·Peregrina, C.·Okuda, K.·Zhou, J. C.·Carrasquero-Ordaz, M.·Roberts, A. V.·Thomas, A. E.·Haanappel, E.·Chavent, M.·el Omari, K.·Baker, L. A.·Pederick, D.·Pardon, E.·Steyaert, J.·Naegerl, U. V.·del Toro, D.·Seiradake, E.

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Abstract

Cortical migration is a complex process in which neurons migrate along radial glial cells (RGC) to form functional layers. Teneurins (Ten1-4) play a role by interacting with Latrophilins (Lphn/ADGRL1-3). Teneurins are also known as cell adhesion molecules, but how homophilic and heterophilic Teneurin interactions are integrated is unknown. Here, single-particle-cryo-EM data of Ten2 shows that canonical Latrophilin-binding is sterically incompatible with Ten2-dimerisation, making these interactions exclusive. We engineered surface mutations that specifically disrupt Ten2-Ten2 or Ten2-Latrophilin interactions. These are transferrable to Ten4, suggesting conserved binding mechanisms. Proteomics, in-vivo-gene-editing and super-resolution-microscopy show that Ten4 is expressed along RGC fibres and that migrating neurons switch from low-to-high Ten4-expression. Ten4 expression is highest in the cortical plate where Ten4-Ten4 interactions reduce RGC-attachment. In the intermediate zone, Ten4-Latrophilin interactions are required to promote neuron-RGC association. The results show how Ten4 orchestrates cortical migration by exclusive structural mechanisms, underpinning the integration of distinct migration programmes. Note: the adhesion GPCR ADGRL is largely referred to as Latrophilin, which is in line with previous papers in the Teneurin field. We would be happy to implement a different naming scheme if recommended.

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Berbeira-Santana, M., Peregrina, C., Okuda, K., Zhou, J. C., Carrasquero-Ordaz, M., Roberts, A. V., Thomas, A. E., Haanappel, E., Chavent, M., el Omari, K., Baker, L. A., Pederick, D., Pardon, E., Steyaert, J., Naegerl, U. V., del Toro, D., Seiradake, E.. 2025-09-10. Teneurin-4 switches between self-recognition and canonical Latrophilin binding to direct neuronal migration. https://doi.org/10.1101/2025.09.09.671438

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