Failure of CNS neurons to mount a significant growth response after trauma contributes to chronic functional deficits after spinal cord injury. Activator and repressor screening of embryonic cortical neurons and retinal ganglion cells in vitro and transcriptional profiling of developing CNS neurons harvested in vivo have identified several candidates that stimulate robust axon growth in vitro and in vivo . Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environment in vivo . We transcriptionally profiled intact sprouting adult corticospinal neurons (CSNs) after contralateral pyramidotomy (PyX) in nogo receptor-1 knockout mice and found that intact CSNs were enriched in genes in the 3-phosphoinositide degradation pathway, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K ( Inpp5k ) could enhance corticospinal tract axon growth in preclinical models of acute and chronic CNS trauma. Overexpression of Inpp5k i...