Structurally exclusive Teneurin complexes orchestrate divergent programs in early cortical development
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.
Authors
- Jan Steyaert (ORCID: https://orcid.org/0000-0002-3825-874X)
- Els Pardon (ORCID: https://orcid.org/0000-0002-2466-0172)
- Daniel del Toro (ORCID: https://orcid.org/0000-0002-7416-2155)
- Lindsay A. Baker (ORCID: https://orcid.org/0000-0001-9578-4263)
- Miguel Berbeira-Santana (ORCID: https://orcid.org/0000-0002-3044-8063)
- Kamel El Omari (ORCID: https://orcid.org/0000-0003-3506-6045)
- Claudia Peregrina (ORCID: https://orcid.org/0000-0002-6710-3616)
- Elena Seiradake
- Evert Haanappel
- J. Zhou
- U. Valentin Nägerl (ORCID: https://orcid.org/0000-0001-6831-9008)
- Kosuke Okuda (ORCID: https://orcid.org/0000-0002-0186-3102)
- Matthieu Chavent (ORCID: https://orcid.org/0000-0003-4524-4773)
- Daniel T. Pederick (ORCID: https://orcid.org/0000-0003-1870-9475)
- Anne E. Thomas (ORCID: https://orcid.org/0000-0002-2808-6462)
- Amy V. Roberts
- Maria Carrasquero-Ordaz
Institutions
- Centre National de la Recherche Scientifique (FR)
- Howard Hughes Medical Institute (US)
- Université Toulouse III - Paul Sabatier (FR)
- Vrije Universiteit Brussel (BE)
- Université de Bordeaux (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- Diamond Light Source (GB)
- University of Oxford (GB)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- Universitätsmedizin Göttingen (DE)
- Institut d'Investigacions Biomèdiques de Barcelona (ES)
- Institut Interdisciplinaire de Neuroscience (FR)
- VIB-VUB Center for Structural Biology (BE)
- Laboratoire de Microbiologie et Génétique Moléculaires (FR)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-04-16
- DOI
- https://doi.org/10.1038/s41467-026-71619-1
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome