Mechanism of NGF-induced formation of axonal filopodia: NGF turns up the volume, but the song remains the same?

The formation of axon collateral branches is a fundamental aspect of the development of neuronal circuits. Emergence of axonal filopodia from the axon is the first step in the formation of axon collateral branches and pre-synaptic structures. Using embryonic sensory axons as a model system, we have determined that axonal filopodia are formed from transient accumulations of F-actin within the axon, termed actin patches. We found that the branch-inducing factor NGF induces the formation of axonal actin patches and filopodia. NGF signaling, through PI3K, promotes the formation of localized axonal microdomains of PIP3 accumulation. The microdomains in turn drive formation of actin patches. Under basal conditions, only a subset of actin patches gives rise to filopodia, and many patches dissipate without forming a filopodium. Neither NGF nor direct activation of PI3K affects the probability that an actin patch will give rise to a filopodium. Thus, NGF increases formation of axonal filopodia through localized PI3K signaling that promotes the initiation of actin patch precursors to the formation of axonal filopodia. The promotion of actin patch formation by NGF may be mediated through a PI3K-TOR pathway driving intra-axonal protein synthesis. We propose the hypothesis that NGF signaling "turns up the volume" on the mechanism of filopodial formation by increasing axonal levels of the cytoskeletal proteins required for the orchestration of actin patch formation by PIP3 microdomains.