The central nervous system (CNS), which is composed of the brain and the spinal cord, controls most of the functions of the human body and mind, including voluntary and involuntary movement, and is responsible for our thoughts, perceptions and emotions. The basic functional units of the nervous system are neurons (nerve cells). These electrically excitable cells communicate with other neurons through specialized connections called synapses. The CNS is composed of an extensive network of ~86 billion connected neurons organized into specific interconnected regions with defined functions. Neurons form connections via long extensions that send out (axons) or receive (dendrites) electrical signals. The establishment of connections over large distances between different brain regions, relies on precise pathfinding capabilities of individual neurons during embryonic development. For example, callosal axons that connect the two halves of the brain (via a thick nerve tract, called the corpus callosum), must navigate a complex trajectory to reach all the way across the brain. Navigation relies on a structure at the tips of neuronal extensions, termed the growth cone, which is able to detect a variety of guidance molecules (such as netrin) that function like traffic cops to guide axons and dendrites to their targets. Dysfunction of neuronal navigation has been linked to numerous neurodevelopmental disorders such as Hirschsprung’s disease, Kallmann syndrome, ACC as well as autism spectrum disorders and epilepsy, and is frequently associated with mutations in genes that encode known navigation machinery components. However, in the majority of cases, the causes of these disorders are unknown, and this is in part because we lack a complete mechanistic understanding of this complex process. Improving our understanding of neuronal guidance will not only enable more accurate diagnosis of these disorders, it could also improve our ability to develop more accurate organ-on-chip models. Objectives of this Marie Skłodowska Curie Action (MSCA) have been to (a) identify the protein components of the neuronal navigation machinery that sense and respond to netrin signals, (b) to determine where these proteins localize within actively moving neurons, and (c) to develop new ways to control the navigation machinery, and neuronal navigation.
