NERVE GROWTH FACTOR INDUCES MITOCHONDRIAL FISSION THAT IS REQUIRED FOR AXON BRANCHING

Abstract

The formation of axon collateral branches from the pre-existing shafts of axons is an important aspect of neurodevelopment and the response of the nervous system to injury. Both the actin filament and microtubule components of the cytoskeleton are required for the formation of axon branches. Recent work has begun to shed light on how these two elements of the cytoskeleton are integrated by proteins that functionally or physically link the cytoskeleton. While a number of signaling pathways have been determined as having a role in the formation of axon branches, the complexity of the downstream mechanisms and links to specific signaling pathways remain to be fully determined. Neurotrophins are growth factors that have a multitude of roles in the nervous system. In sensory neurons nerve growth factor (NGF) induces branching through activation of phosphoinositide 3-kinase (PI3K). Recently, mitochondria have emerged as major determinants of the sites of axon branching. In this work we reveal a new role of neurotrophins in mitochondria fission. We report that NGF promote a rapid burst of mitochondria fission, followed by a new steady state of mitochondria length and density. Mek- Erk and PI3k pathways are required for NGF-induced fission. Mek-Erk controls fission through Drp1 activation, while we suggest that PI3K may contributes to the actin dependent aspect of fission. Drp1 mediated fission is required for NGF- induced branching in sensory neurons in vitro and the branching of sensory axons along the developing spinal cord. We reveal that fission is also required for the intra-axonal translation of the actin regulatory proteins Cortactin and Arp2 subunit from the Arp2/3 complex, an important aspect of NGF induced branching. Collectively, these observations reveal a novel role of neurotrophins in mitochondria fission and the formation of collateral branching