My aim is to explore the subcellular (i.e. cell biological and molecular) mechanisms of axon loss in the developing and diseased mammalian nervous system. Axon loss not only sculpts neuronal networks in development, but also occurs early in numerous neurological diseases. Indeed, the life-time risk for diseases with an “axonopathic” component approaches 50%. Pathological axon loss likely involves aberrant activation of developmental programs – just as cell death in disease often takes the form of apoptosis, another prominent regressive event in neural development. Over the past few years, the first molecular pathways have emerged for one form of axon loss, Wallerian degeneration, which removes entire axon arbors after severing. However, Wallerian degeneration is of limited clinical significance – because the axon is cut and hence incapacitated before it is lost – and appears to play only minor roles in development. In contrast, “non-Wallerian” forms of axon loss that selectively remove individual “aberrant” branches dominate during development (“axon branch loss”). Due to the technical challenge of studying axon loss in the complex environment of the developing mammalian nervous system, the subcellular events that precede such non-Wallerian forms of axon branch loss are poorly understood, even though this phenomenon – when pathologically reactivated – likely contributes to axonal pathology in many neurological disorders. Over the past years, in parallel work on axon development and disease, my laboratory has devised functional imaging techniques that allow studying axon loss in vivo in the mammalian peripheral (PNS) and central nervous system (CNS) with subcellular resolution and molecular read-outs. Using these unique tools, I will address the following aims:1 - Axon-intrinsic mechanisms of motor axon branch loss.2 - Axon-glial mechanisms of motor axon branch loss.3 - Axon branch loss during CNS development.4 - Axon branch loss after CNS injury.