Microtubule-destabilizing enzymes in healthy and pathological development of neuronal circuits

The mature nervous system is an intricate network in which precise connectivity between neurons is critical for the accurate functioning of the system. Neuronal connectivity is established during development by successive steps of axon outgrowth/navigation, synapse formation and pruning of exuberant connections and only undergoes limited remodelling in the mature nervous system. Ectopic or imprecise connections during development can lead to major neurological disorders extending from brain malformation to psychiatric disorders. A crucial step in the assembly of neuronal circuits lies in the ability of developing axons to navigate accurately toward their appropriate targets. This complex task is achieved by the growth cone machinery, a cytoskeleton-based structure that senses extracellular guidance signals and translates them into growth cone mechanical behaviours. While microtubules recently emerged as key driving forces of growth cone steering, the numerous players that regulates microtubule remodelling in navigating axons, as well as their specific mode of action and regulation by guidance cues remain largely unknown. Yet, the exponentially growing number of neurodevelopmental disorders associated with mutations in genes encoding the microtubule building block (i.e., tubulin dimers), microtubule-modifying enzymes or -interacting proteins emphasizes the need to identify the protein networks that regulate microtubule functions in developing neurons.
Over the last past years, our team pioneered the use pluri-disciplinary and multi-system approaches combined with advanced microscopy to dissect the role of microtubule destabilizing enzymes – involved in neurological disorders – in the shaping of neuronal connectivity at molecular, cellular and circuit scales. These conceptual and methodological approaches enabled us to provide important new insights into the molecular mechanisms governing microtubule functions in healthy and pathological development of neuronal circuits. It has further opened novel avenues for the development of therapeutic strategies to prevent axonal degeneration or rather promote directed axon (re)growth in pathological conditions.

Host: Marie-Jo Moutin.