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Subcellular second messenger networks drive distinct repellent-induced axon behaviors.

ABSTRACT: Second messengers, including cAMP, cGMP and Ca²⁺ are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca²⁺ changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 and Slit1, induce spatially segregated signals. These guidance molecules activate subcellular-specific second messenger crosstalk, each signaling network controlling distinct axonal morphology changes in vitro and pathfinding decisions in vivo.

SUBMITTER: Baudet S

PROVIDER: S-EPMC10300027 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Subcellular second messenger networks drive distinct repellent-induced axon behaviors.

Baudet Sarah S Zagar Yvrick Y Roche Fiona F Gomez-Bravo Claudia C Couvet Sandrine S Bécret Johann J Belle Morgane M Vougny Juliette J Uthayasuthan Sinthuya S Ros Oriol O Nicol Xavier X

Nature communications 20230627 1

Second messengers, including cAMP, cGMP and Ca<sup>2+</sup> are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca<sup>2+</sup> changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 a ...[more]

PMID: 37369692

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Project description:BackgroundThe PAM/Highwire/RPM-1 (PHR) proteins are conserved signaling proteins that regulate axon length and synapse formation during development. Loss of function in Caenorhabditis elegans rpm-1 results in axon termination and synapse formation defects in the mechanosensory neurons. An explanation for why these two phenotypes are observed in a single neuronal cell has remained absent. Further, it is uncertain whether the axon termination phenotypes observed in the mechanosensory neurons of rpm-1 mutants are unique to this specific type of neuron, or more widespread defects that occur with loss of function in rpm-1.ResultsHere, we show that RPM-1 is localized to both the mature axon tip and the presynaptic terminals of individual motor neurons and individual mechanosensory neurons. Genetic analysis indicated that GABAergic motor neurons, like the mechanosensory neurons, have both synapse formation and axon termination defects in rpm-1 mutants. RPM-1 functions in parallel with the active zone component SYD-2 (Liprin) to regulate not only synapse formation, but also axon termination in motor neurons. Our analysis of rpm-1-/-; syd-2-/- double mutants also revealed a role for RPM-1 in axon extension. The MAP3K DLK-1 partly mediated RPM-1 function in both axon termination and axon extension, and the relative role of DLK-1 was dictated by the anatomical location of the neuron in question.ConclusionsOur findings show that axon termination defects are a core phenotype caused by loss of function in rpm-1, and not unique to the mechanosensory neurons. We show in motor neurons and in mechanosensory neurons that RPM-1 is localized to multiple, distinct subcellular compartments in a single cell. Thus, RPM-1 might be differentially regulated or RPM-1 might differentially control signals in distinct subcellular compartments to regulate multiple developmental outcomes in a single neuron. Our findings provide further support for the previously proposed model that PHR proteins function to coordinate axon outgrowth and termination with synapse formation.

Dataset Information

Subcellular second messenger networks drive distinct repellent-induced axon behaviors.

Publications

Subcellular second messenger networks drive distinct repellent-induced axon behaviors.

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