Heterotopia genes help us understand progenitor cell function during cortical development

DELFINA ROMERO; FRANCIS, FIONA; KARINE POIRIER; NADIA BAHI BUISSON

Congreso; FENS 2020 Virtual Forum; 2020

Federación de Sociedades Europeas de Neurociencia

Cerebral cortical development is a finely regulated process that depends on several different progenitor types. The ventricular zone (VZ) of the developing cortex is a neuroepithelium that contains neural stem cells (NSCs), undergoing precisely regulated divisions at its most apical, ventricular side. These cells can self-amplify and produce other progenitor types, as well as immature neurons. Perturbations of these processes lead to severe cortical malformations in human. Subcortical heterotopias are malformations associated with epilepsy and intellectual disability. They are characterized by ectopic neurons in the white matter. Elucidating the underlying patho-mechanisms can shed light on the regulation and function of progenitors and migrating neurons during cortical development. Mouse models of heterotopia are rare, although mouse and human mutations were identified in the microtubule-binding protein EML1. Using genetic strategies, 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 VZ from early corticogenesis and interacts with key VZ proteins. In utero electroporation of Dlgap4 knockdown and overexpression constructs in the mouse embryonic brain revealed a perturbed ventricular surface, as well as changes in cell fate, proliferation and migration. We further show that Dlgap4 molecular mechanisms involve the actin cytoskeleton and mTOR signaling pathways. In this way we are identifying new heterotopia-linked molecular pathways playing a crucial role in regulating progenitors of the VZ.