Inositol Polyphosphate-5-Phosphatase K (Inpp5k) Enhances Sprouting of Corticospinal Tract Axons after CNS Trauma

Abstract

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 cellsin vitroand transcriptional profiling of developing CNS neurons harvestedin vivohave identified several candidates that stimulate robust axon growthin vitroandin vivo. Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environmentin vivo. We transcriptionally profiled intact sprouting adult corticospinal neurons (CSNs) after contralateral pyramidotomy (PyX) in nogo receptor-1 knock-out 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 (CST) axon growth in preclinical models of acute and chronic CNS trauma. Overexpression ofInpp5kin intact adult CSNs in male and female mice enhanced the sprouting of intact CST terminals after PyX and cortical stroke and sprouting of CST axons after acute and chronic severe thoracic spinal contusion. We show thatInpp5kstimulates axon growth in part by elevating the density of active cofilin in labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. We identifyInpp5kas a novel CST growth activator capable of driving compensatory axon growth in multiple complex CNS injury environments and underscores the veracity of usingin vivotranscriptional screening to identify the next generation of cell-autonomous factors capable of repairing the damaged CNS.SIGNIFICANCE STATEMENTNeurologic recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post-trauma.In vitroscreening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growthin vivo, concomitant functional recovery remains incomplete. We identifiedInpp5kas a novel axon growth activator using transcriptional profiling of intact adult corticospinal tract (CST) neurons that had initiated a growth response after pyramidotomy in plasticity sensitized nogo receptor-1-null mice. Here, we show thatInpp5koverexpression can stimulate CST axon growth after pyramidotomy, stroke, and acute and chronic contusion injuries. These data supportin vivoscreening approaches to identify novel axon growth activators.