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

ROMERO, DM; POIRIER, K; BELVINDRAH, R; MOUTKINE, I; HOULLIER, A; LE MOING, A-G; PETIT, F; BOLAND, A; COLLINS, SC; SOIZA-REILLY, M; YALCIN, B; CHELLY, J; DELEUZE, JF; BAHI-BUISSON, N; FRANCIS, F

NATURE COMMUNICATIONS

SPRINGER NATURE

Lugar: LONDRES; Año: 2022 vol. 13

2041-1723

Subcortical heterotopias are malformations associated with epilepsy and intellectual disability,characterized by the presence of ectopic neurons in the white matter. Mouse andhuman heterotopia mutations were identified in the microtubule-binding protein Echinodermmicrotubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, weidentified 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 inglutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricularzone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. Inutero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed aventricular surface phenotype including changes in progenitor cell dynamics, morphology,proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wildtype but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial celladherens junction components and actin cytoskeleton dynamics at the apical domain, as wellas during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also showdevelopmental defects in the dorsal telencephalon. We hence identify a synapse-relatedscaffold protein with pleiotropic functions, influencing the integrity of the developing cerebralcortex.