PROJECT SUMMARY The branching of axons is a pivotal event in the development of neuronal circuitry and during the response of the nervous system to injury. We and others recently identified a crucial role for axonal mitochondria in axon branching. This proposal aims to advance the understanding of the role of mitochondria in axon branching and axonal physiology. The preliminary data unveil that nerve growth factor, a branch inducing signal, promotes the fission of axonal mitochondria which is in turn required for the ensuing branching. The PI3K signaling pathway is necessary and sufficient for the induction of fission by NGF. Aim 1 of this proposal aims to determine whether neurotrophins which induce branching in vivo also induce fission and the role of fission in in vivo branching, and further dissect the signaling mechanism used by NGF to drive the fission of axonal mitochondria. Aim 2 will address the role of the axonal cytoskeleton in the regulation of mitochondrial fission. Aim 3 will seek to determine how the fission of mitochondria contributes to axonal physiology and the mechanism of axon branching. Collectively, these aims have the potential to make impactful advances which will be of interest to a wide community of scientists.