A novel phosphatase regulating neurite extension on CNS inhibitors

The inability of injured axons to regenerate in the adult mammalian central nervous system is thought to be in part due to inhibitory molecules synthesized by oligodendrocytes and present in myelin. We describe the cloning of a cDNA encoding a novel neuronal protein, named NERPP-2C, which is distantly related to protein phosphatase 2C and plays a role in the inhibitory response pathway to myelin inhibitors. NERPP-2C is expressed in neuronal cell lines and in rat brain. Expression in rat is detectable at E15, increases with age, and is highest in adulthood. Exposure of NG108-15 cells to antisense oligonucleotides reduces NERPP-2C expression and overcomes the inhibition of neurite extension on CNS myelin substrates in vitro. Antibodies to NERPP-2C detect two proteins, approximately 55 and 80 kDa in size, the smaller of which is found in the cytoplasm, and the larger is associated with the membrane fraction. The antibodies specifically immunoprecipitate a protein which exhibits serine/threonine and tyrosine phosphatase activity. NERPP-2C is localized in neurites and in growth cones, as well as in the cell nucleus. We hypothesize that NERPP-2C is a component in the signal transduction pathway for neuronal growth inhibitory factors in CNS myelin.