NOVEL ROLE OF THE SYNAPTIC SCAFFOLD PROTEIN DLGAP4 IN THE VENTRICULAR SURFACE INTEGRITY AND NEURONAL MIGRATION DURING CORTICAL DEVELOPMENT

DELFINA M. ROMERO; KARINE POIRIER; RICHARD BELVINDRAH; IMANE MOUTKINE; ANNE HOULLIER; ANNE-GAELLE LE MOING; FLORENCE PETIT; ANNE BOLAND; MARIANO SOIZA REILLY; BINNAZ YALCIN; JAMEL CHELLY; JEAN FRAÇOIS DELEUZE; NADIA BAHI BUISSON; FIONA FRANCIS

Congreso; Reunión Conjunta SOCIEDADES DE BIOCIENCIAS 2021; 2021

Subcortical heterotopias are malformations associatedwith epilepsy and intellectual disability, characterizedby the presence of ectopic neurons in the white matter.Mouse and human heterotopia mutations were identifiedin the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploringpathological mechanisms, we identified a patient with anEML1-like phenotype and a novel genetic variation in DLGAP4.The protein belongs to a membrane-associatedguanylate kinase family known to function in glutamatesynapses. We show that DLGAP4 is strongly expressedin the mouse ventricular zone (VZ) from early corticogenesis,and interacts with key VZ proteins including EML1.In utero electroporation of Dlgap4 knockdown (KD) andoverexpression constructs revealed a ventricular surfacephenotype including changes in progenitor cell dynamics,morphology, proliferation and neuronal migrationdefects. The Dlgap4 KD phenotype was rescued by wildtypebut not mutant DLGAP4. Dlgap4 is required for theorganization of radial glial cell adherens junction componentsand actin cytoskeleton dynamics at the apicaldomain, as well as playing a critical role during neuronalmigration. We hence identify a synapse-related scaffoldprotein with pleiotropic functions in the telencephalicneuroepithelium, influencing the overall integrity of thedeveloping cerebral cortex.