Description du projet
Profilage des agents de circulation moléculaires et des cellules migrantes qu’ils dirigent
La migration cellulaire, soit individuelle soit en groupe, a lieu tout au long du développement embryonnaire. Le dysfonctionnement de ce processus a été associé à de nombreux troubles neurodéveloppementaux, ainsi qu’aux troubles du spectre autistique et à l’épilepsie. Les agents de circulation qui dirigent cette migration sont des nétrines capables d’attirer ou de repousser les cellules migrantes, dirigeant ainsi leur mouvement dans des points de contrôle intermédiaires. Cela semble être lié au type et au nombre de récepteurs des nétrines présents aux extrémités des extensions neuronales, mais les mécanismes réels ne sont pas bien compris. Le projet LAMININ, financé par l’UE, prévoit de les élucider grâce à des études sur les complexes récepteur-nétrine, et sur la localisation et l’activité des protéines à l’intérieur des cônes de croissance neuronale en mouvement.
Objectif
Proper wiring and connectivity of the central and peripheral nervous system requires that during embryonic development neurons migrate and extend in the correct directions to connect to their targets. Defects in the neuronal navigation machinery lead to a variety of neurodevelopmental disorders such as Hirschsprung’s disease, Kallmann syndrome, ACC and has been associated with autism spectrum disorders and epilepsy. Neuronal navigation relies on a structure at the tips of neuronal extensions, termed the growth cone which is able to detect gradients of guidance molecules (chemotactants) secreted by cells at a distance. The chemotactant netrin, which binds multiple netrin receptors, can switch between attracting and repelling growth cones, a property which helps neurons change directionality upon reaching an intermediate target. While it has been demonstrated that this is related to the complement of netrin receptors expressed by the neuron, it is unclear how different receptor combinations trigger opposing directional responses within the growth cone. It was recently shown that aberrant expression of netrin receptors in cells that don’t normally express it cause aberrant migration of neurons, which might explain some of the symptoms associated with neurodevelopmental disorders such as Mowat-Wilson syndrome. This proposal aims to understand at the molecular level how netrin can both attract and repel neuronal growth cones. This will be accomplished by mapping the interactome of both attractive and repulsive netrin-receptor complexes, and by mapping the spatial distribution and activity of proteins within actively steering growth cones, via high resolution microscopy, micropatterning and optogenetics to spatially modulate protein activities. This combinatorial approach will improve our understanding of neuronal guidance, associated disorders, and new technologies developed in this proposal might aid in the development of novel organ-on-chip technology.
Champ scientifique
- natural sciencesbiological sciencesneurobiology
- medical and health sciencesbasic medicineneurologyepilepsy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesdevelopmental biology
- engineering and technologyother engineering and technologiesmicrotechnologyorgan on a chip
Programme(s)
Régime de financement
MSCA-IF-EF-RI - RI – Reintegration panelCoordinateur
3015 GD Rotterdam
Pays-Bas