PROJECT: JTC2015: STEM-MCD

The human cerebral cortex is a highly organized structure, with layers and folds which are formed in still little-understood ways. Specialized stem and neuronal progenitor cells, and precise neuronal migration pathways, form the basis of this structure. Cortical malformations can arise characterized by a smooth brain surface, disorganized layers and aberrantly positioned neurons, which are associated with untreatable epilepsy and intellectual disability. These disorders are currently modeled in the rodent with limited success. Recent data from our laboratories, studying existing models, have pointed to progenitor abnormalities, a relatively unexpected cause of these disorders. Our groups aim to shed further light on the behavior of progenitors and neurons in health and disease. We will analyze human brain sections, exploit novel genetic tools to amplify progenitor number and influence neuronal organization in the mouse, and combine the most recent in vitro technologies of reprogramming, self-organization and directed differentiation of human cells (patient and control), analyzed by state-of-the-art imaging techniques. We hypothesize that variable perturbations of progenitors and migration contribute to different cortical phenotypes and we will systematically study these processes in our models. Learning more about human neuronal cells and their perturbations in malformations, we will also search for molecular targets, with a view to correcting cellular pathomechanisms.