Integrin adhesome axis inhibits the RPM-1 ubiquitin ligase signaling hub to regulate growth cone and axon development

Jonathan Amezquita, Muriel Desbois, Karla J Opperman, Joseph S Pak, Elyse L Christensen, Nikki T Nguyen, Karen Diaz-Garcia, Melissa A Borgen and Brock Grill

PLOS Genetics, 2024, vol. 20, issue 12, 1-30

Abstract: Integrin signaling plays important roles in development and disease. An adhesion signaling network called the integrin adhesome has been principally defined using bioinformatics and cell-based 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 (TLN-1), Kindlin (UNC-112) and β-integrin (PAT-3). C. elegans RPM-1 is orthologous to human MYCBP2, a prominent player in nervous system development recently associated with a neurodevelopmental disorder. After curating and updating the conserved C. elegans adhesome, we identified an adhesome subnetwork physically associated with RPM-1 that has extensive links to human neurobehavioral abnormalities. Using neuron-specific, CRISPR loss-of-function strategies, we demonstrate that a PAT-3/UNC-112/TLN-1 adhesome axis regulates axon termination in mechanosensory neurons by inhibiting RPM-1. Developmental time-course studies and pharmacological results suggest TLN-1 inhibition of RPM-1 affects growth cone collapse and microtubule dynamics during axon outgrowth. These results indicate the PAT-3/UNC-112/TLN-1 adhesome axis restricts RPM-1 signaling to ensure axon outgrowth is terminated in a spatially and temporally accurate manner. Thus, our findings orthogonally validate the adhesome using an organismal setting, identify an adhesome axis that inhibits RPM-1 (MYCBP2), and highlight important new links between the adhesome and brain disorders.Author summary: The adhesome is an important signaling network in development that has been principally defined using bioinformatics and proteomics with cell-lines. We have used C. elegans as a whole animal model to orthogonally identify and evaluate an adhesome subnetwork that regulates axon development. Our studies demonstrate that an Integrin/Kindlin/Talin adhesome axis influences axon development by regulating termination of axon outgrowth. Mechanistically, this occurs via the Integrin/Kindlin/Talin axis inhibiting the RPM-1 ubiquitin ligase signaling hub to influence microtubule and growth cone dynamics. RPM-1 and its human homolog MYCBP2 are prominent evolutionarily conserved regulators of nervous system development and associated with a neurodevelopmental disorder. Our findings validate the adhesome using an organismal setting, identify an adhesome axis that inhibits RPM-1 (MYCBP2), and highlight extensive genetic links between the adhesome and abnormal human neurodevelopment.

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1011496

DOI: 10.1371/journal.pgen.1011496

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