Structurally exclusive Teneurin complexes orchestrate divergent programs in early cortical development

Miguel Berbeira-Santana, Claudia Peregrina, Kosuke Okuda, Jin Chuan Zhou, Maria Carrasquero-Ordaz, Amy V. Roberts, Anne E. Thomas, Evert Haanappel, Matthieu Chavent, Kamel el Omari, Lindsay A. Baker, Daniel T. Pederick, Els Pardon, Jan Steyaert, U. Valentin Nägerl, Daniel del Toro, Elena Seiradake
Nature Communications. 2026-04-16; 17(1):
DOI: 10.1038/s41467-026-71619-1

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 different stages of cortical migration by using a structural/functional switch between high-affinity Lphn interactions and low-affinity homophilic interactions, underpinning the integration of distinct migration programmes.