Final Report Summary - NEVAI (Neurovascular Interactions and Pathfinding in the Spinal Motor System) In this project, we have investigated how neurons and blood vessels establish matched networks that are an anatomical feature of virtually every organ and tissue in our body. The spatial overlap between nerves and vessels underscores their tight functional interdependency, which is often affected in neurological disorders. We took a developmental perspective to examine the molecular basis of neurovascular association using the mouse embryo as a model system. Through genetic and transcriptional screens, we have identified genes and factors that control the trajectory of developing nerves and vessels and coordinate their interactions. We made the unexpected discovery that neuronal projections are not only guided to their synaptic targets by instructive signals expressed along their paths, but they also need to silence responsiveness to mock signals that would trigger inappropriate pathfinding responses, steering nerves off track. We characterized one of such “noise-filtering” systems and showed that it is required to allow spinal motor axons to leave the spinal cord to reach muscles, which is the essential guidance decision of this class of neurons that connect the central nervous system to peripheral organs. When this link is interrupted, commands from the brain cannot be relayed to muscles –a condition reminiscent of diseases affecting the spinal motor system, including Amyotrophic lateral sclerosis. The study of mouse mutants with defects in both nerve and vessel patterning led to the discovery of a biochemical mechanism that governs crosstalk between the two systems. Through cell-based assays, gene profiling and computational analysis we built models that account for precise and reciprocal nerve-vascular communication, which we demonstrate to be necessary for setting up congruent networks during embryonic development. These findings prompt investigation of the newly identified neurovascular pathways in maintenance of neuronal connectivity in adults.