The synaptic scaffold protein Dlgap4 is important for progenitor cell function during cortical development

ROMERO DM; BAHI-BUISSON, N; POIRIER, K; LE MOING, A.G; CHELLY, J; DELEUZE JF; FRANCIS F

Buenos Aires

Congreso; Latin American Society of Developmental Biology Meeting 2019; 2019

Latin American Society Developmental Biology

Grey matter heterotopias are common malformations of cortical development associated with epilepsy and intellectual disability. We have recently identified EML1, a microtubule-binding protein, as a gene responsible for giant subcortical heterotopias in human and mouse. Further exploring pathophysiological mechanisms, we have identified a key patient with giant heterotopia and a novel variation in DLGAP4, using whole exome and Sanger sequencing. A second family showed several gene variations including DLGAP4 and DLGAP1. DLGAP4 belongs to a membrane-associated guanylate kinase family known for its function in synapses. We show that DLGAP4 interacts with EML1, is expressed in the mouse progenitor cells from early corticogenesis and interacts with key ventricular zone proteins, including DLG1 and LGN. In utero electroporation of Dlgap4 knockdown and overexpression constructs revealed a strong ventricular zone phenotype, as well as changes in cell fate, proliferation and migration. We further show DLGAP4 molecular mechanisms involve the actin cytoskeleton and mTOR signaling pathways. Thus, this scaffolding protein, previously linked to autism spectrum disorder, also plays a role in progenitor cells and ventricular surface integrity during cortical development. We emphasize that so-called ?synaptic? genes and associated protein complexes can be involved in wider mechanisms than previously thought, and may be considered as candidates for a larger spectrum of neurological disorders.Oral Presentation