Axon formation, extension, and navigation: only a neuroscience phenomenon?

Abstract

Understanding how neurons form, extend, and navigate their finger-like axonal and dendritic processes is crucial for developing therapeutics for the diseased and damaged brain. Although less well appreciated, many other types of cells also send out similar finger-like projections. Indeed, unlike neuronal specific phenomena such as synapse formation or synaptic transmission, an important issue for thought is that this critical long-standing question of how a cellular process like an axon or dendrite forms and extends is not primarily a neuroscience problem but a cell biological problem. In that case, the use of simple cellular processes - such as the bristle cell process of Drosophila - can aid in the fight to answer these critical questions. Specifically, determining how a model cellular process is generated can provide a framework for manipulations of all types of membranous process-containing cells, including different types of neurons.

Figure 1.. Neurons and other membranous process-containing cells.

(A) Neurons are the best-known of the membranous process-containing cells – but are also the most complex. Adapted from [88]. (B) Many different types of cells – including those within the nervous, cardiovascular, immune, and musculoskeletal systems – send out membranous extensions/processes. Many of these other process-containing cells are much simpler than neurons. The mechanisms of this process extension and the means to control it, so as to stimulate re-extension of neuronal processes or inhibit the extensions of metastasizing cancer cells, for example, are poorly understood. Adapted from [–103].

Figure 2.. Control of F-actin and microtubule dynamics drive neuronal form and function.

(A–C) Neuronal extension, shape, connectivity, and function (A) is driven by regulating the ability of single actin proteins (G-actin) to form filaments (F-actin) (B) and single alpha (α) and beta (β) tubulin proteins to form microtubules (C). (D) Signals from the cell surface, such as from different guidance cues and their receptors control F-actin and microtubule (MT) dynamics through poorly understood means.

Figure 3.. Development and morphology of membranous process extension and navigation.

(A–D) The extension of cellular processes (arrows) – from neutrophil (A) and mesenchymal (B) cells in vitro to bristle (C) and neuronal (D) cells in vivo. Adapted from [,–106]. (E) Note also the means by which axons extend “new” processes/change the direction of their process extension – via a new protrusion/filopodium (E, left arrow), which then forms the new growing cellular process/axon (E, right arrow). Adapted from [87].

Figure 4.. The bristle cell as a simple membranous process-containing cell.

(A–B) The bristle cell with its long process provides a model cellular process. (A) Note the long single cell bristle processes on the body of the adult fly (e.g., each arrow points to a single bristle cell with its process). Images reproduced with permission from [74]. (B, left) The stereotypical arrangement of F-actin and microtubules pushes out the bristle process during pupal development. (B, right) The bristle cell also secretes a chitin cuticle that wraps around its cellular process – preserving a record in the adult of its developmental history and allowing a rapid initial characterization (in different contexts and genetic backgrounds) without requiring tissue processing. (C–D) Changing Mical levels alters bristle process extension and morphology – including (D) inducing it to resemble an axon growth cone. Images reproduced with permission from [74,76,107]. (E–F) Sema (on dendrite) interacts with Plexin (on bristle), to activate Mical within the bristle to induce cellular remodeling and branching (F; [74]). (F) This remodeling and branching occurs through the disassembly of F-actin (green) within bristle processes (2), which then allows currently unknown factors to form this actin-rich branch (3). (G–H) The Sema/Plexin/Mical-induced bristle branching (H, arrow) is remarkably similar to an axon’s response in vivo to a repellent (G, arrow). In particular, the axon’s (growth cone’s) response is to decrease in size (G, compare 37mins to 50 and 56mins) and then form a new “back” branch (G, arrow) [87] – which is the same response seen in the bristle upon Mical activation (H; [74]). Image reproduced with permission from [87].