Semaphorin heterodimerization in cis regulates membrane targeting and neocortical wiring

Paraskevi Bessa, Andrew G. Newman, Kuo Yan, Theres Schaub, Rike Dannenberg, Denis Lajkó, Julia Eilenberger, Theresa Brunet, Kathrin Textoris-Taube, Emanuel Kemmler, Penghui Deng, Priyanka Banerjee, Ethiraj Ravindran, Robert Preissner, Marta Rosário and Victor Tarabykin ()
Additional contact information
Paraskevi Bessa: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Andrew G. Newman: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Kuo Yan: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Theres Schaub: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Rike Dannenberg: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Denis Lajkó: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Julia Eilenberger: Dr. von Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-Universität München
Theresa Brunet: Ludwig Maximilians University
Kathrin Textoris-Taube: Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Philippstrasse 12
Emanuel Kemmler: Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Philippstrasse 12
Penghui Deng: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Priyanka Banerjee: Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Philippstrasse 12
Ethiraj Ravindran: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Robert Preissner: Charité -Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Philippstrasse 12
Marta Rosário: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1
Victor Tarabykin: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-51009-1

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