Mechanistic advances in axon pathfinding

Abstract

The development of a functional nervous system entails establishing connectivity between appropriate synaptic partners. During axonal pathfinding, the developing axon navigates through the extracellular environment, extending toward postsynaptic targets. In the early 1900s, Ramon y Cajal suggested that the growth cone, a specialized, dynamic, and cytoskeletal-rich structure at the tip of the extending axon, is guided by chemical cues in the extracellular environment. A century of work supports this hypothesis and introduced myriad guidance cues and receptors that promote a variety of growth cone behaviors including extension, pause, collapse, retraction, turning, and branching. Here, we highlight research from the last two years regarding pathways implicated in axon pathfinding.

Keywords: Cytoskeleton; Dendritic spines; Growth cone; Guidance cues; Mechanotransduction; Membrane trafficking; Post-translational modification.

Figure 1.. Recent research in growth cone motility.

Although guidance cues, mechanotransduction, cytoskeleton reorganization, and calcium signaling holistically contribute to growth cone motility, we’ve selected several new discoveries in each of these categories to highlight here. (A) New work highlights contribution of adhesion molecules (CD166 enhances Sema3C-mediated axon branching), combinatorial effects (Ephrin-A5 signaling increases Neogenin surface expression and downstream Netrin-1 signaling) and both haptotactic and soluble signaling (Netrin-1) in axon guidance. (B) Mechanotransduction influences motility, both by the generation of traction force on the ECM (L1CAM) and the activation of Piezo and TRP channels by stretching of the plasma membrane. (C) Coupling of the microtubule and actin cytoskeletons in the growth, newly shown to be mediated by XMAP215 and DAAM1. (D) Post-translational modifications facilitate rapid changes in filopodial formation and stability, as indicated by phosphorylation of cortactin and VASP ubiquitination. (E) Calcium signaling is required for growth cone remodeling. Recent work includes: microtubule organization is regulated by STIM1, calpain cleavage of FAK, talin and DCC, and PKC-mediated Myosin-II activation promotes cofilin recruitment and actin severing.

Figure 2.. Dendritic filopodia and dendritic spine.

(A) Dendritic filopodia. Like in the growth cone, formin proteins have been observed at the tips of filopodia, elongating actin filaments. However, unlike in the growth cone, dendritic filopodia are known to contain the branching Arp2/3 complex and capping protein, while lacking the actin-bundling protein fascin. Sustained Eph-B signaling (following axonal EphrinB binding) facilitates synaptogenesis. (B) Dendritic spine. Numerous and diverse cell adhesion molecules facilitate synaptic maturation and plasticity, by connecting the pre- and post-synapse (along with the ECM) and contributing to signaling pathway activation. Netrin signaling via the DCC receptor leads to downstream Src signaling required for long-term potentiation. NMDAR signaling results in the calcium-dependent activation of CaMKII, activating numerous cytoskeleton proteins including cofilin (leading to actin severing and depolymerization), RhoA (leading to myosin activation) and Cdc42 (ultimately leading to Arp2/3 mediated actin branching). The actin cytoskeleton of the dendritic spine is predominantly branched, akin to the lamellipodia, with formin and VASP-mediated protrusions.