Posttranslational Modification of Sox11 Regulates RGC Survival and Axon Regeneration

Abstract

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 in vitro . Here, we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. In vitro , 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 in vivo 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 Spp1 and Opn4 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.

Influence of Sox protein SUMOylation on neural development and regeneration

“…Over the past decade, RNA sequencing (RNA-seq) technology facilitates transcriptome-wide analysis, which is capable of examining gene sliced transcripts, PTMs and singlenucleotide polymorphisms (Stark et al, 2019). A previous RNA-Seq study revealed that SUMOylation of Sox11 regulates RGC survival and axon regeneration by activating different signaling pathways (Chang et al, 2021). Using such a technology would provide a deeper understanding of SUMO regulatory mechanism in neural development and neurological disease.…”

“…In RGC progeny, Sox11 is SUMOylated at K91 and expressed mainly in the cytoplasm while deSUMOylated Sox11 (Sox11 K91R ) is mostly in the nucleus, and blocking Sox11 SUMOylation enhances RGC differentiation . In addition, exogenous overexpression of a non-SUMOylatable Sox11 mutant (Sox11 K91A ) promotes more axon regeneration in vivo but reduces spp1 + and opn4 + gene expression in early postnatal primary RGC cultures (Chang et al, 2021). In addition, SoxC TFs also affect Muller glia development , a process which may similarly depend on protein SUMOylation.…”

“…In regard to gene therapy, overexpression of a SUMO site mutant gene was applied to PRE65-mice by subretinal AAV2 injection, showing a restorative phenotype (Maurya et al, 2019). Growing evidence on intravitreal AAV injection shows the therapeutic benefits of promoting axon regeneration by knocking down Krüppel-like transcription factor 9 (Moore et al, 2009) or overexpressing a non-SUMOylatable Sox11 mutant (Sox11 K91A ) (Chang et al, 2021). Clustered regularly interspaced short palindromic repeats (CRISPR) technology can specifically modify, delete or correct precise regions of DNA, which is thought to be a potential method to treat genetic diseases.…”

The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina

“…Other intrinsic regenerative genes and pathways include Wnt signaling [114], Lin28 [115], Sry-related high-mobility-box 11 [116], Krüppel-like factor 4/9 [117], histone deacetylase [118], c-myc [119], and cAMP [93,120]. However, a single manipulation of these pathways or these genes is not enough for promoting long-lasting optic nerve regeneration in vivo.…”

The Role of Lipids, Lipid Metabolism and Ectopic Lipid Accumulation in Axon Growth, Regeneration and Repair after CNS Injury and Disease

“…As neurons mature, however, a development dependent decline in the expression of genes controlling axon growth is, at least in part, responsible for axon regeneration failure in the adult [ 64 , 65 ]. In turn, the identification of positive regulators and molecular mechanisms controlling axon growth and regeneration has been the subject of intensive investigation [ 12 , 25 , 66 , 67 , 68 , 69 , 70 ]. In exploring the mechanisms that control intrinsic axon growth, a recent study has discovered that the stemness-associated gene Prom1, which encodes the membrane glycoprotein Prominin-1, acts as a positive regulator of peripheral nerve regeneration in adulthood [ 71 ].…”