Figure 8.

Diagram showing the effects of CSPGs on components of the mechanism of axon branching and the effects of promoting mitochondrial function with ALC. (A) Summary schematic of the contribution of axonal mitochondria to the regulation of axonal cytoskeletal and filopodial dynamics. (B–D) In each panel the relative “strength” of the activation of components of the mechanism of axon branching is denoted by arrows which depict relative strength by their color and size (shown in the bottom left of the figure). (B) NGF strongly drives signaling pathways (e.g., PI3K, Erk), promotes mitochondrial respiration (Verburg and Hollenbeck, 2008) and drives intra-axonal protein synthesis. The arrow between mitochondria and translation reflect the role of mitochondrial function in the promotion of axonal translation (Spillane et al., 2013). Ultimately, signaling, mitochondria function and axonal translation converge on the axonal cytoskeleton to promote branch formation. A connection between signaling pathways and the regulation of mitochondria function and translation is not shown, for clarity, but implied as both of these components of the mechanism of branching are also under regulation by signaling pathways (see Discussion). (C) In the absence of NGF activation of the components of branching is minimal. In this context promotion of mitochondrial function with ALC is unable to further drive branching. (D) In the presence of NGF but on CSPG coated substrata the activation of components of the branching mechanism is attenuated, but persists at moderate levels (Fisher et al., 2011; Silver et al., 2014). In this background, promotion of mitochondrial function with ALC is able to promote branching by working cooperatively with the available signaling and translational mechanisms while promoting the mitochondria respiration dependent aspects of the broader mechanism (blue).