Apical trafficking in neural progenitors in health and disease

This project explores understudied mechanisms of brain development. Apical radial glia are key stem cells required for cerebral cortex development, greatly influencing final brain architecture and function. These are polarized cells with apical (ventricular) and basal (superficial) processes and attachments. This project is focused on the apical extremity, containing proteins and lipids essential for proliferation, cell attachment and polarity. This cell compartment is important for several reasons. It allows a communication with the cerebrospinal fluid. In addition, cortical developmental disorders (e.g. heterotopia associated with severe epilepsy and intellectual disability) can arise by the loss of apical attachments. Neocortex evolution is also associated with an increase of basal radial glia, generally no longer attached apically. The mechanisms for such changes impacting apical extremities of radial glia remain unclear. We hypothesize that protein and lipid trafficking play an essential role. Our preliminary data provides new entry points to study apical process dynamics. We have identified rare mutations in patients with heterotopia, epilepsy and /or intellectual disability, pinpointing proteins influencing trafficking. This includes a lectin galactoside-binding soluble 3 binding protein, LGALS3BP, as well as a ceramide synthase, CERS6 never studied previously during cortical development. LGALS3BP mutations perturb extracellular vesicle biogenesis and dysregulate trafficking proteins, altering secretion and extracellular composition. The family of CERS lipid regulating proteins, localized in secretory compartments, influences membrane composition and protein localization, as well as signalling pathways. These proteins are likely to play a central role in radial glial biology. Converging interests of the Francis (Paris) and Cappello (Munich) labs, lead us to develop and characterize in vitro and in vivo models to dissect and compare the roles of these proteins. We collaborate closely with Bahi-Buisson (Paris) for the identification of new gene mutations in cortical malformation patients. Our labs are very well recognized in the cortical development and malformation fields, with previous work converging on deciphering disrupted cell biology pathways in cortical progenitor cells and neurons. Our objectives in this new project (organized in three work packages, WPs, each involving multiple groups) are to assess and identify: 1. Anterograde trafficking in apical radial glia, focusing on secretory mechanisms and apical membranes 2. Retrograde trafficking in the same cells, focusing on vesicle endocytosis and assimilation by the cell 3. New mutations in trafficking genes giving rise to neurodevelopmental disorders. An important goal is to systematically compare and study trafficking, membranes and organelles of apical radial glia incorporating different patient mutations. Our combined studies will reveal substantial new data for the novel question of the role of protein and lipid trafficking in nervous system development and function. We will identify causal gene mutations to help diagnose and classify malformations and neurodevelopmental disorders in patients.

Overview

Grant agreement ANR-25-CE16-0505 | APICAL-TRAFFIC