Semaphorin heterodimerization in cis regulates membrane targeting and neocortical wiring
Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.
Authors
- Theresa Brunet (ORCID: https://orcid.org/0000-0002-5183-780X)
- Penghui Deng
- Victor Tarabykin (ORCID: https://orcid.org/0000-0001-8931-7263)
- Emanuel Kemmler (ORCID: https://orcid.org/0009-0008-2046-823X)
- Kathrin Textoris‐Taube (ORCID: https://orcid.org/0000-0002-1224-8236)
- Priyanka Banerjee (ORCID: https://orcid.org/0000-0001-8072-5594)
- Robert Preißner (ORCID: https://orcid.org/0000-0002-2407-1087)
- Rike Dannenberg
- Paraskevi Bessa (ORCID: https://orcid.org/0000-0003-1469-5686)
- Julia Eilenberger
- Denis Lajkó
- Marta Rosário (ORCID: https://orcid.org/0000-0003-1101-7177)
- Andrew G. Newman (ORCID: https://orcid.org/0000-0002-0222-9162)
- Kuo Yan (ORCID: https://orcid.org/0000-0001-7769-0802)
- Ethiraj Ravindran (ORCID: https://orcid.org/0000-0002-0095-116X)
- Theres Schaub (ORCID: https://orcid.org/0000-0003-0790-5040)
Institutions
- TUM Klinikum (DE)
- Humboldt-Universität zu Berlin (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Technical University of Munich (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- N. I. Lobachevsky State University of Nizhny Novgorod (RU)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1038/s41467-024-51009-1
- Citations
- 6
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Russian Science Foundation