Differential Role of PTEN Phosphatase in Chemotactic Growth Cone Guidance

Negatively targeting the tumor suppressor and phosphoinositide phosphatase PTEN promotes axon re-growth after injury. How PTEN functions in axon guidance has remained unknown. Here we report the differential role of PTEN in chemotactic guidance of axonal growth cones. Downregulating PTEN expression in Xenopus laevis spinal neurons selectively abolished growth cone chemorepulsion but permitted chemoattraction. These findings persisted during cAMP-dependent switching of turning behaviors. Live-cell imaging using a GFP biosensor revealed rapid PTEN-dependent depression of phosphatidylinositol 3,4,5-trisphosphate (PIP3) levels in the growth cone induced by the repellent myelin-associated glycoprotein (MAG). Moreover, downregulating PTEN expression blocked negative remodeling of β1-integrin adhesions triggered by MAG, yet permitted integrin clustering by a positive chemotropic treatment. Thus, PTEN negatively regulates growth cone PIP3 levels and mediates chemorepulsion, whereas chemoattraction is PTEN independent. Regenerative therapies targeting PTEN may therefore suppress growth cone repulsion to soluble cues while permitting attractive guidance, an essential feature for re-forming functional neural circuits.