AC BREAKS THE SPHERE · The physiological role of ADF/cofilin in neuronal development

Beginning life as simple symmetric spheres, neurons undergo a complicated morphogenesis until they become integrated in functional neuronal networks. A neurons development involves migration, neuritogenesis, polarization, and axon guidance. Each of these processes relies heavily on the reorganization of the underlying cytoskeleton. From cultured neurons and invertebrates, progress has been made in identifying signalling proteins that modulate the cytoskeleton during different stages of neuronal development. Despite the progress, questions remain regarding the physiological relevance of these molecules during neuronal development in mammals. ADF/cofilin proteins (AC proteins) have been implicated in regulating actin during various phases of neuronal development. Here, we outline our plans to study the role of AC proteins during in vivo development and in regulating actin dynamics during neurite formation using the brain-specific double knockout of ADF/Cofilin in mice. These studies will provide a greater understanding of the specific role of AC proteins during neuronal development and reveal how the organization and kinetics of actin changes during neurite formation and growth. Specifically, this work will: 1) characterize the developmental consequences of AC ablation in vivo, ex vivo and in culture, 2) determine what changes occur to the actin cytoskeleton with and without AC proteins during neuritogenesis, and 3) determine the genetic relationships of AC proteins during neurite formation. The proposed work will entail a multi-directional transfer of knowledge in advancing the conceptual understanding of neuronal development and in sharing technical expertise to and from the proposed fellow, the host institution, and the European Neuroscience community at large. The work is highly significant because it will elucidate mechanisms underlying brain development, an important issue at the intersection of cell and developmental biology and neurobiology.