Wiring of the nervous system during development sets the pattern of connections that allow the organism to function in the world. The proper formation of neural circuitry is orchestrated by co-occurrence of progressive events, such as axonal guidance and branching, and regressive events in which axons and neurons are eliminated. Although wiring errors underly a variety of neurodevelopmental disorders, the mechanisms that govern this complex phenomenon are largely unknown. In the Yaron lab, we are studying these mechanisms, exploring the functional and behavioral outcomes of miswiring, and examining how genetic wiring programs are modulated by experience.
Early in development, each newly-sprouted axon needs to extend and connect to its traget. How do axons know to navigate through the body, often over large distances, to find their appropriate targets? Molecules in the extracellular environment, called guidance cues, control this directional growth. These cues activate receptors on the responding axons at the right time and place to trigger signaling cascades that steer the axons in the correct direction. However, the nature of these cascades is poorly understood. We are combining in vitro axonal guidance assays and state-of-the-art mouse genetics to uncover how guidance cues direct growing axons to their targets.
Once the initial pattern of the nervous system has been established, refinement takes place. A major contributor to this is axonal elimination, which is essential for normal development of the nervous system. However, the mechanisms that regulate this process are elusive. We are using a variety of in vivo assays combined with cellular and molecular analyses to shed light on the pathways that control axonal breakdown in the CNS and PNS, and examining the behavioral consequences of deregulated axonal pruning.
Interplay between genetics and experience
One of the key questions in neuroscience is how the balance between “nature” and “nurture” shapes the wiring of the brain. The molecular basis of this interplay is largely unknown. Specifically, the hippocampus is a brain region strongly linked with experience-dependent plasticity. We are investigating how developmental genetic programs and life events integrate to dictate synapse elimination and axonal pruning in the developing hippocampus.