Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

Delfina M. Romero, Karine Poirier, Richard Belvindrah, Imane Moutkine, Anne Houllier, Anne-Gaëlle LeMoing, Florence Petit, Anne Boland, Stephan C. Collins, Mariano Soiza-Reilly, Binnaz Yalcin, Jamel Chelly, Jean-François Deleuze, Nadia Bahi-Buisson and Fiona Francis ()
Additional contact information
Delfina M. Romero: INSERM UMR-S 1270
Karine Poirier: Paris Cité University, Necker Enfants Malades University Hospital
Richard Belvindrah: INSERM UMR-S 1270
Imane Moutkine: INSERM UMR-S 1270
Anne Houllier: INSERM UMR-S 1270
Anne-Gaëlle LeMoing: Service of Pediatric Neurology, CHU Amiens
Florence Petit: Department of Clinical Genetics. Hôpital Jeanne de Flandre, CHU Lille
Anne Boland: University Paris-Saclay
Stephan C. Collins: University of Bourgogne Franche-Comté
Mariano Soiza-Reilly: Universidad de Buenos Aires
Binnaz Yalcin: University of Bourgogne Franche-Comté
Jamel Chelly: IGBMC-CNRS UMR-S 7104, INSERM UMR-S 964
Jean-François Deleuze: University Paris-Saclay
Nadia Bahi-Buisson: Laboratory of Genetics and Development of the Cerebral Cortex, INSERM UMR-S 1163, Imagine Institute
Fiona Francis: INSERM UMR-S 1270

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.

Date: 2022
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DOI: 10.1038/s41467-022-30443-z

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