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

• Published in: The Journal of neuroscience 2022-03, Vol.42 (11), p.2190-2204
• Main Authors: Kauer, Sierra D, Fink, Kathryn L, Li, Elizabeth H F, Evans, Brian P, Golan, Noa, Cafferty, William B J
• Format: Article
• Language: English
• Subjects: Actin; Animals; Axon sprouting; Axons; Axons - metabolism; Cofilin; Cones; Embryos; Female; Filopodia; Growth cones; In vivo methods and tests; Inositol - metabolism; Inositol polyphosphate; Inositols; Male; Mice; Mice, Inbred C57BL; Nerve Regeneration - physiology; Neurons; Nogo protein; Phosphatase; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Polyphosphates - metabolism; Pyramidal tracts; Pyramidal Tracts - physiology; Retinal ganglion cells; Screening; Spinal Cord Injuries; Thorax; Transcription; Trauma
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.0897-21.2022

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 and transcriptional profiling of developing CNS neurons harvested have identified several candidates that stimulate robust axon growth and Building on these studies, we sought to identify novel axon growth activators induced in the complex adult CNS environment 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 ( ) could enhance corticospinal tract (CST) axon growth in preclinical models of acute and chronic CNS trauma. Overexpression of in 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 that stimulates 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 identify as a novel CST growth activator capable of driving compensatory axon growth in multiple complex CNS injury environments and underscores the veracity of using transcriptional screening to identify the next generation of cell-autonomous factors capable of repairing the damaged CNS. Neurologic recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post-trauma. screening 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 growth , concomitant functional recovery remains incomplete. We identified as 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 that overexpression can stimulate CST axon growth after pyramidotomy, stroke, and acute and chronic contusion injuries. These data support screening approaches to identify novel axon growth activators.