Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons
Citations Over TimeTop 14% of 2015 papers
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.
Related Papers
- → A dual inhibitor against prolyl isomerase Pin1 and cyclophilin discovered by a novel real-time fluorescence detection method(2011)37 cited
- → The Multiple Roles of Peptidyl Prolyl Isomerases in Brain Cancer(2018)11 cited
- → Small Molecule Inhibitors of Peptidylprolyl cis/trans Isomerase(2010)6 cited
- Molecular structure and regulate mechanisms of the peptidyl prolyl cis/trans isomerase Pin1(2009)
- → Pin1: a catalyst of the tumorigenesis of malignant neoplasms(2016)