Abstract
The cerebral cortex comprises diverse excitatory and inhibitory neuron subtypes, each with distinct laminar positions and connectivity patterns. Yet, the molecular logic underlying their precise wiring remains poorly understood. To identify ligand–receptor (LR) interactions involved in cortical circuit assembly, we tracked gene expression dynamics in mice across major neuronal populations at 17 developmental stages using single-cell transcriptomics. This generated a comprehensive atlas of LR-mediated communication between excitatory and inhibitory neuron subtypes, capturing known and novel interactions. Notably, we identified NEOGENIN-1 as the principal receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneuron…
Abstract
The cerebral cortex comprises diverse excitatory and inhibitory neuron subtypes, each with distinct laminar positions and connectivity patterns. Yet, the molecular logic underlying their precise wiring remains poorly understood. To identify ligand–receptor (LR) interactions involved in cortical circuit assembly, we tracked gene expression dynamics in mice across major neuronal populations at 17 developmental stages using single-cell transcriptomics. This generated a comprehensive atlas of LR-mediated communication between excitatory and inhibitory neuron subtypes, capturing known and novel interactions. Notably, we identified NEOGENIN-1 as the principal receptor for CBLN4 during the perinatal period, mediating synapse formation between somatostatin-expressing interneurons and glutamatergic neurons. We also identified members of the cadherin superfamily as candidate regulators of perisomatic inhibition from parvalbumin-expressing basket cells onto deep and superficial excitatory neurons, exerting opposing effects on synapse formation. These findings suggest a context-dependent role for cadherins in synaptic specificity and underscore the power of single-cell transcriptomics for decoding the molecular mechanisms of cortical wiring.
Data availability
Raw sc/snRNA-seq data generated in this study are available in the ArrayExpress database under accession E-MTAB-16260, and bulk RNA-seq data are available under accession E-MTAB-16355 (https://www.ebi.ac.uk/biostudies/arrayexpress/studies). Processed data, QC outputs, and derived RDS files are deposited on Zenodo (https://zenodo.org/records/11634657). Interactive exploration of inferred signaling networks is available through the scLRSomatoDev Shiny application at https://sclrsomatodev.online/. Source data are provided with this paper.
Code availability
All scripts used for data preprocessing, quality control, ligand–receptor inference, ontology annotation, and enrichment analysis were written in R and Python. The complete codebase, including custom functions and documentation, is publicly available on Zenodo (https://zenodo.org/records/11634657). Additional documentation and tutorials are provided online: Documentation: https://cortical-interactome.github.io/scLRSomatoDev-Docs/ Video tutorials: https://www.youtube.com/playlist?list=PLyfGSyn6Q6UY82ccuHRZQmRchVx6DskfJ.
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Acknowledgements
We thank Julien Prados (UNIGE) for providing his Torch model for artificial neural network (ANN)-based cell type identification, members of the Cardoso laboratory for their input, and the Molecular and Cellular Biology Facility (PBMC), the Animal Core Facility and the Imaging Facility (inMagic) INMED platforms. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale de la Recherche with ANR-13-JSV4-0006 SynD2 and ANR-23-CE16-0021 CALIN (A.d.C.), NeuroMarseille ICR+ Grant 2021 (A.d.C.), Fondation pour la Recherche sur le Cerveau ‘Développement et vieillissement’ (A.d.C.), Fondation Lejeune (A.d.C.), European Community 7th Framework programs (Development and Epilepsy; Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy [DESIRE], Health-F2-602531-2013 (A. R., C.C.), and by an Excellence Initiative of Aix–Marseille University/A*MIDEX grant (CALIN-R24002AA) of the French ‘Investissements d’Avenir’ programme (C.C., A.d.C.). Research in the Telley laboratory was supported by ERC starting grant CERDEV_759112 and a SNSF grant 31003A_182676/1.
Author information
Author notes
These authors jointly supervised this work: Ludovic Telley, Antoine de Chevigny.
Authors and Affiliations
INMED, INSERM, Aix Marseille University, Marseille, France
Rémi Mathieu, Tangra Draia-Nicolau, Léa Corbières, Annousha Govindan, Vianney Bensa, Emilie Pallesi-Pocachard, Lucas Silvagnoli, Alfonso Represa, Carlos Cardoso & Antoine de Chevigny 1.
Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
Ludovic Telley 1.
University Claude Bernard Lyon 1, MeLiS; UCBL; CNRS UMR 5284, Lyon, France
Ludovic Telley
Authors
- Rémi Mathieu
- Tangra Draia-Nicolau
- Léa Corbières
- Annousha Govindan
- Vianney Bensa
- Emilie Pallesi-Pocachard
- Lucas Silvagnoli
- Alfonso Represa
- Carlos Cardoso
- Ludovic Telley
- Antoine de Chevigny
Contributions
A.d.C. and R.M. initiated the study. A.d.C. and L.T. conceptualized and supervised the study. A.d.C., L.T. and R.M. designed and conceptualized the experiments. A.d.C. L.T and R.M. performed most experiments. R.M. analyzed most experiments, supervised by L.T. and A.d.C. T.D.N. performed analyses for Figs. 3 and 4 and revision analysis. R.M. and L.S generated the Shiny App scLRSomatodev (https://sclrsomatodev.online/). C.C., A.G., L.C. and V.B. performed and analyzed shRNA design/production and in utero electroporations. E.P. validated shRNAs and performed proximity ligation assays. A.R participated in project management and help in manuscript writing and corrections. A.d.C. L.T. and R.M. wrote the manuscript with input from all authors.
Corresponding authors
Correspondence to Ludovic Telley or Antoine de Chevigny.
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Mathieu, R., Draia-Nicolau, T., Corbières, L. et al. Uncovering the molecular logic of cortical wiring between neuronal subtypes across development through ligand–receptor inference. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68059-8
Received: 09 May 2025
Accepted: 16 December 2025
Published: 22 January 2026
DOI: https://doi.org/10.1038/s41467-025-68059-8