The formation of axon collateral branches underlies the ability of neurons to make synaptic contacts with multiple target neurons and thus give rise to complex neuronal networks. In the context of nervous system injury, the formation of axon collateral branches can have either beneficial or undesired effects depending on the affected circuitry. Collateral branches are also affected by a variety of disease states. However, the cellular mechanisms of collateral branching are only minimally understood. The preliminary data presented in this proposal unveils for the first time that the branch-inducing signal nerve growth factor drives the intra-axonal synthesis of cytoskeletal proteins with roles in the formation of collateral branches. Importantly, the preliminary data also demonstrate that axonal protein synthesis is required for the induction of axon collateral branching by nerve growth factor. Although recent studies have revealed a large set of mRNAs targeted to axons, the functional roles of the axonal translation of axonal mRNAs remains minimally understood. The main aim of the proposal is to determine the roles of the axonal synthesis of individual cytoskeletal proteins in the formation of axon collateral branches. By bridging the expertise of the PI (Dr. Gallo;neuronal cytoskeletal cell biology) and the Co-I (Dr. Twiss;axonal protein synthesis), the project provides the unique opportunity to uncover a new aspect of the mechanism of axon branching and aims to directly link the axonal synthesis of specific cytoskeletal proteins to the regulation f the dynamics of the axonal cytoskeleton. Through the joint expertise of the PI and Co-I, the project takes a multi-pronged in vivo and in vitro approach to address the main Aims. Collateral branching is affected by nervous system injury and disease. However, the ability to manipulate branching in a therapeutic context is mostly lacking. The project has the potential to lead to strategies for the regulation of axon branching by targeting specific axonal mRNA species in the context of neuronal injury and disease. The reagents developed for use in the project (e.g., cell permeable tools to selectively inhibit the axonal translation of individual mRNA species) have the potential for translation to animal model system of collateral branching in future directions o the project. The work we propose will serve as the foundation for these long term goals by determining the relevant mRNA targets through the elucidation of their roles in branching.
Axon branching is fundamental to the development and plasticity of the nervous system. In this proposal, we address the hypothesis that intra-axonal synthesis of cytoskeletal proteins is required for the regulation of the formation of axon branches and filopodia by extracellular signals.
|Smith, George M; Gallo, Gianluca (2018) The role of mitochondria in axon development and regeneration. Dev Neurobiol 78:221-237|
|Sainath, Rajiv; Ketschek, Andrea; Grandi, Leah et al. (2017) CSPGs inhibit axon branching by impairing mitochondria-dependent regulation of actin dynamics and axonal translation. Dev Neurobiol 77:454-473|
|Sainath, Rajiv; Armijo-Weingart, Lorena; Ketscheck, Andrea et al. (2017) Chondroitin sulfate proteoglycans negatively regulate the positioning of mitochondria and endoplasmic reticulum to distal axons. Dev Neurobiol 77:1351-1370|
|Armijo-Weingart, Lorena; Gallo, Gianluca (2017) It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches. Mol Cell Neurosci 84:36-47|
|Pacheco, Almudena; Gallo, Gianluca (2016) Actin filament-microtubule interactions in axon initiation and branching. Brain Res Bull 126:300-310|
|Winkle, Cortney C; Taylor, Kendra L; Dent, Erik W et al. (2016) Beyond the cytoskeleton: The emerging role of organelles and membrane remodeling in the regulation of axon collateral branches. Dev Neurobiol 76:1293-1307|
|Ketschek, Andrea; Spillane, Mirela; Dun, Xin-Peng et al. (2016) Drebrin coordinates the actin and microtubule cytoskeleton during the initiation of axon collateral branches. Dev Neurobiol 76:1092-110|
|Gallo, Gianluca (2016) Coordination of the axonal cytoskeleton during the emergence of axon collateral branches. Neural Regen Res 11:709-11|
|Sainath, Rajiv; Gallo, Gianluca (2015) The dynein inhibitor Ciliobrevin D inhibits the bidirectional transport of organelles along sensory axons and impairs NGF-mediated regulation of growth cones and axon branches. Dev Neurobiol 75:757-77|
|Sainath, Rajiv; Gallo, Gianluca (2015) Cytoskeletal and signaling mechanisms of neurite formation. Cell Tissue Res 359:267-78|
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