Novel role of the synaptic scaffold protein Dlgap4 from early stages of cortical development

DELFINA M. ROMERO; KARINE POIRIER; RICHARD BELVINDRAH; IMANE MOUTKINE; ANNE HOULLIER; MARIANO SOIZA-REILLY; BINNAZ JALCIN; JAMEL CHELLY; NADIA BAHI-BUISSO; FIONA FRANCIS

Virtual meeting

Congreso; NeuroFrance 2021; 2021

Société des Neurosciences

Subcortical heterotopias are malformations associated with epilepsy and intellectual disability. They are characterized by ectopic neurons in the white matter suggesting abnormal neuronal migration. Mouse models of this disorder are rare, although mouse and human mutations were identified in the microtubule-binding protein EML1. Further exploring pathological mechanisms, we identified a novel patient heterotopia variation in DLGAP4. This protein belongs to a membrane-associated guanylate kinase family known to function in synapses. We show it interacts with EML1, is expressed in the mouse ventricular and intermediate zones as well as the developing cortical plate from early corticogenesis. In utero electroporation of Dlgap4 knockdown and overexpression constructs revealed defects in cell fate, proliferation and migration. The knockdown phenotype was rescued by wild-type but not mutant DLGAP4. Furthermore, we identify a role for Dlgap4 in actin cytoskeleton dynamics and signaling in cortical cells. We have hence characterized a synapse-related scaffold protein playing an important role in cortical progenitors which support neuronal migration. Using these approaches, we can piece together molecular and cellular determinants regulating progenitor and neuron function during cortical development.