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Spatially and temporally accurate termination of axon outgrowth, a process called axon termination, is required for efficient, precise nervous system construction and wiring. The mechanosensory neurons that sense low-threshold mechanical stimulation or gentle touch have proven exceptionally valuable for studying axon termination over the past 40 years. In this Review, we discuss progress made in deciphering the molecular and genetic mechanisms that govern axon termination in touch receptor neurons. Findings across model organisms, including Caenorhabditis elegans, Drosophila, zebrafish and mice, have revealed that complex signaling is required for termination with conserved principles and players beginning to surface. A key emerging theme is that axon termination is mediated by complex signaling networks that include ubiquitin ligase signaling hubs, kinase cascades, transcription factors, guidance/adhesion receptors and growth factors. Here, we begin a discussion about how these signaling networks could represent termination codes that trigger cessation of axon outgrowth in different species and types of mechanosensory neurons.

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Integrin signaling plays important roles in development and disease. An adhesion signaling network called the integrin adhesome has been principally defined using bioinformatics and proteomics. To date, the adhesome has not been studied using integrated proteomic and genetic approaches. Here, proteomic studies in C. elegans identified physical associations between the RPM-1 ubiquitin ligase signaling hub and numerous adhesome components including Talin, Kindlin and beta-integrin. C. elegans RPM-1 is orthologous to human MYCBP2, a prominent player in nervous system development associated with a neurodevelopmental disorder. Using neuron-specific, CRISPR loss-of-function strategies, we show that core adhesome components affect axon development and interact genetically with RPM-1. Mechanistically, Talin opposes RPM-1 in a functional 'tug-of-war' on growth cones that is required for accurate axon termination. Thus, our findings orthogonally validate the adhesome via multi-component genetic and physical interfaces with a key neuronal signaling hub and identify new links between the adhesome and brain disorders.

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Axon termination is essential for efficient and accurate nervous system construction. At present, relatively little is known about how growth cone collapse occurs prior to axon termination in vivo Using the mechanosensory neurons of C. elegans, we found collapse prior to axon termination is protracted, with the growth cone transitioning from a dynamic to a static state. Growth cone collapse prior to termination is facilitated by the signaling hub RPM-1. Given the prominence of the cytoskeleton in growth cone collapse, we assessed the relationship between RPM-1 and regulators of actin dynamics and microtubule stability. Our results reveal several important findings about how axon termination is orchestrated: (1) RPM-1 functions in parallel to RHO-1 and CRMP/UNC-33, but is suppressed by the Rac isoform MIG-2; (2) RPM-1 opposes the function of microtubule stabilizers, including tubulin acetyltransferases; and (3) genetic epistasis suggests the microtubule-stabilizing protein Tau/PTL-1 potentially inhibits RPM-1. These findings provide insight into how growth cone collapse is regulated during axon termination in vivo, and suggest that RPM-1 signaling destabilizes microtubules to facilitate growth cone collapse and axon termination.

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During development, a coordinated and integrated series of events must be accomplished in order to generate functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1) function in each of these events in development. Here, we review PHR function across species, as well as the myriad of signaling pathways PHR proteins regulate. These findings collectively suggest that the PHR proteins are intracellular signaling hubs, a concept we explore in depth. Consistent with prominent developmental functions, genetic links have begun to emerge between PHR signaling networks and neurodevelopmental disorders, such as autism, schizophrenia and intellectual disability. Finally, we discuss the recent and important finding that PHR proteins regulate axon degeneration, which has further heightened interest in this fascinating group of molecules.

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