New insights into the molecular mechanisms of axon guidance receptor regulation and signaling

Abstract

As the nervous system develops, newly differentiated neurons need to extend their axons toward their synaptic targets to form functional neural circuits. During this highly dynamic process of axon pathfinding, guidance receptors expressed at the tips of motile axons interact with soluble guidance cues or membrane tethered molecules present in the environment to be either attracted toward or repelled away from the source of these cues. As competing cues are often present at the same location and during the same developmental period, guidance receptors need to be both spatially and temporally regulated in order for the navigating axons to make appropriate guidance decisions. This regulation is exerted by a diverse array of molecular mechanisms that have come into focus over the past several decades and these mechanisms ensure that the correct complement of surface receptors is present on the growth cone, a fan-shaped expansion at the tip of the axon. This dynamic, highly motile structure is defined by a lamellipodial network lining the periphery of the growth cone interspersed with finger-like filopodial projections that serve to explore the surrounding environment. Once axon guidance receptors are deployed at the right place and time at the growth cone surface, they respond to their respective ligands by initiating a complex set of signaling events that serve to rearrange the growth cone membrane and the actin and microtubule cytoskeleton to affect axon growth and guidance. In this review, we highlight recent advances that shed light on the rich complexity of mechanisms that regulate axon guidance receptor distribution, activation and downstream signaling.

Mapping of pituitary stress-induced gene regulation connects Nrcam to negative emotions

“…This pathway and these terms include processes involved in neuron morphogenesis and neuron communication, thus the DETs in these processes could be important for translating the pituitary molecular stress response. By further dissecting the Reactome pathway ''Nervous system development'', we found that most DETs (30/ 31) could be mapped to the pathway ''Axon Guidance'', which describes the process by which neurons send out axons to reach their synaptic target (Zang et al, 2021). As shown in the heatmap, the majority of the upregulated DETs in this pathway code for ribosomal proteins (Figure 2B).…”

With the Permission of Microtubules: An Updated Overview on Microtubule Function During Axon Pathfinding

“…During the last years, our understanding of the molecular mechanisms and proteins involved in the cytoskeletal transduction of axon guidance signaling has greatly progressed. While the list of upstream guidance cues and receptor families has not significantly grown, novel combinatorial mechanisms involved in signal transduction and cytoskeleton-regulatory proteins recipient of guidance information are continuously emerging ( Stoeckli, 2018 ; Zang et al, 2021 ). Among the latter, Microtubule-Associated Proteins (MAPs) represent a significant group.…”

“…During pathfinding GCs are simultaneously exposed to various signaling proteins and the final guidance decision relies on the spatial-temporal repertoire of guidance receptors expressed at the surface and the computation of their downstream signaling pathways. In addition, neuron-intrinsic molecular mechanisms including response-modulating co-receptors, receptor-receptor interactions, receptor clustering and oligomerization, proteolytic processing of receptors, or the trafficking of signaling receptors-carrying endosomes, contribute to the diversification of axonal responses to a same guidance cue ( Dudanova and Klein, 2013 ; Pasterkamp and Burk, 2021 ; Zang et al, 2021 ). These intracellular pathways ultimately converge on proteins managing the cytoskeleton remodeling in the axon and GC.…”

Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins

“…Consequent to neuronal maturation, this event, occurring all over the nervous system, regulates refinement of projections and is strongly supported by environmental factors. SEMAs are well-known players in axonal pathfinding [ 72 ], and not surprisingly also mediate their pruning.…”