Letter: Glamourizing the consultant.

Abstract

<h3>Abstract</h3> The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury but exacerbates the death of a subset of retinal ganglion cells (RGCs), α-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent SUMOylation at lysine 91 (K91) increased Sox11 nuclear localization and RGC differentiation <i>in vitro</i>. Here, we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. <i>In vitro</i>, we found that non-SUMOylatable Sox11^K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11^K91A more strongly promotes axon regeneration but also increases RGC death after optic nerve injury <i>in vivo</i> in the adult mouse. RNA sequence (RNA-seq) data showed that Sox11 and Sox11^K91A increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated <i>Spp1</i> and <i>Opn4</i> expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus, Sox11 and its SUMOylation site at K91 regulate gene expression, survival and axon growth in RGCs, and may be explored further as potential regenerative therapies for optic neuropathy.