Cooperation and crosstalk in axon guidance cue integration: Additivity, synergy, and fine‐tuning in combinatorial signaling

Abstract

Neural circuit development involves the coordinated growth and guidance of axons to their targets. Following the identification of many guidance cue molecules, recent experiments have focused on the interactions of their signaling cascades, which can be generally classified as additive or non-additive depending on the signal convergence point. While additive (parallel) signaling suggests limited molecular interaction between the pathways, non-additive signaling involves crosstalk between pathways and includes more complex synergistic, hierarchical, and permissive guidance cue relationships. Here the authors have attempted to classify recent studies that describe axon guidance signal integration according to these divisions. They also discuss the mechanistic implications of such interactions, as well as general ideas relating signal integration to the generation of diversity of axon guidance responses. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 891-904, 2017.

Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

“…Several lines of evidence have shown that Netrin and Slit signals can interact in diverse ways in the different nervous systems, including Slits acting through a co-receptor complex to switch on Netrin attraction for thalamocortical axons, and the opposite effect of Netrin attenuation of Slit repulsion (Bielle et al, 2011; Fothergill et al, 2014; Leyva-Díaz et al, 2014; Morales and Kania, 2016). In addition, the parallel independent Netrin and Slit guidance of fly commissural axons has been reported (Garbe and Bashaw, 2007).…”

A new model for netrin1 in commissural axon guidance

“…All of these cues can—and do—impinge on commissural growth cones simultaneously, not necessarily producing simple additive effects (Butler & Dodd, ; Sloan et al, ). The study of how multiple molecular cascades are integrated to produce a coherent cellular response is an area rich in investigation (reviewed in Dudanova & Klein, ; and in Morales & Kania, ).…”

Epithelial Patterning, Morphogenesis, and Evolution: Drosophila Eggshell as a Model

“…Additionally, combinatorial signaling, or the integration of multiple pathways, is another well-established means to increase the information available to cells from limited numbers of signaling pathways. Combinatorial signaling is used repeatedly in metazoan development, from cell-fate specification to axon guidance (Briscoe and Small, 2015; Cornell and Kimelman, 1994; Flores et al, 2000; Morales and Kania, 2016). …”