Prolyl isomerase Pin1 regulates axon guidance by stabilizing CRMP2A selectively in distal axons

Martin Balastik (Lead / Corresponding author), Xiao Zhen Zhou, Meritxell Alberich-Jorda, Romana Weissova, Jakub Žiak, Maria F. Pazyra-Murphy, Katharina E. Cosker, Olga Machonova, Iryna Kozmikova, Chun-Hau Chen, Lucia Pastorino, John M. Asara, Adam Cole, Calum Sutherland, Rosalind A. Segal, Kun Ping Lu (Lead / Corresponding author)

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    25 Citations (Scopus)
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    Abstract

    Axon guidance relies on precise translation of extracellular signal gradients into local changes in cytoskeletal dynamics, but the molecular mechanisms regulating dose-dependent responses of growth cones are still poorly understood. Here, we show that during embryonic development in growing axons, a low level of Semaphorin3A stimulation is buffered by the prolyl isomerase Pin1. We demonstrate that Pin1 stabilizes CDK5-phosphorylated CRMP2A, the major isoform of CRMP2 in distal axons. Consequently, Pin1 knockdown or knockout reduces CRMP2A levels specifically in distal axons and inhibits axon growth, which can be fully rescued by Pin1 or CRMP2A expression. Moreover, Pin1 knockdown or knockout increases sensitivity to Sema3A-induced growth cone collapse in vitro and in vivo, leading to developmental abnormalities in axon guidance. These results identify an important isoform-specific function and regulation of CRMP2A in controlling axon growth and uncover Pin1-catalyzed prolyl isomerization as a regulatory mechanism in axon guidance.

    Original languageEnglish
    Pages (from-to)812-828
    Number of pages17
    JournalCell Reports
    Volume13
    Issue number4
    Early online date17 Oct 2015
    DOIs
    Publication statusPublished - 27 Oct 2015

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