Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

Abstract

A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either Phosphatase and tensin homolog (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signaling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around two weeks after the crush injury1,2. Remarkably, we now find that simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as a key for sustaining long-distance axon regeneration in adult CNS, a crucial step toward functional recovery.

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…GDF10 signals through TGF-βRI and II and Smad 2/3, to activate PI3 kinase gene systems and to inhibit the signaling of phosphatase and tensin homolog and suppressor of cytokine signaling 3. These gene systems mediate axonal sprouting in other contexts in the adult, such as in optic nerve and spinal cord injury [99][100][101]. These data indicate that GDF10 is one molecule in a trigger after stroke and coordinately activates parallel growth promotion cascades.…”

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

“…The poor intrinsic neuronal growth can be improved by the deletion of phosphatase and tensin homolog and suppressor of cytokine signaling 3 (SOCS3), two key players for cell growth inhibition. 46 …”

B-RAF kinase drives developmental axon growth and promotes axon regeneration in the injured mature CNS

“…In recent years, the optic nerve model has revealed several intracellular signaling pathways that can drive CNS axon regeneration, most prominently the PI3-kinase-mTOR and the JAK-STAT pathways, engaged by growth factor tyrosine kinase receptors and cytokines (Park et al, 2008;Smith et al, 2009;Buchser et al, 2012;Leibinger et al, 2013;Pernet et al, 2013). Combined deletion of endogenous inhibitors of these two pathways enhanced regeneration above the level reported for deletion of either gene alone (Sun et al, 2011). Activation of PI3-kinase-mTOR via PTEN deletion also enhanced regenerative growth in an SCI model , suggesting that results obtained in the optic nerve crush model may generally translate to SCI models.…”

“…Indeed, growth inhibitory signaling molecules such as the SOCS family or phosphatases are up-regulated upon maturation (Lu et al, 2002;Smith et al, 2009;Park et al, 2010;Gatto et al, 2013). Therefore, the most promising studies using growth factors have combined them with genetic intervention to up-regulate growth factor receptors or down-regulate their intrinsic inhibitors (Hollis et al, 2009;Sun et al, 2011). The second issue is that of undesirable side effects, especially that of neuropathic pain caused by neurotrophin administration (Obata et al, 2006;Jankowski and Koerber, 2009).…”