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 Sox11K91A leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11K91A 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 Sox11K91A 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.
Highlights
Restoring neuronal connections and function in degenerative diseases and after injury in the CNS is a critical goal for neuroscience and has been investigated for decades, with only a handful of approaches showing promiseReceived August 16, 2020; accepted December 22, 2020; First published January 13, 2021
We demonstrated that Sry-related high-mobility-box 11 (Sox11) SUMOylation at lysine residue 91 (K91) suppressed its nuclear translocation from the cytoplasm; site mutation of Sox11 to prevent SUMOylation led to higher nuclear localization and to an increase in retinal ganglion cells (RGCs) differentiation from retinal progenitor cells (Chang et al, 2017)
Sox11K91A prevents Sox11 SUMOylation To investigate the effects of Sox11 in vivo, we first designed associated virus (AAV)-backbone plasmids encoding Sox11 and Sox11K91A and verified protein expression level after 3 d of coculture in human embryonic kidney 293 (HEK 293) cells and hippocampal neurons by immunostaining (Fig. 1A) and Western blotting (Fig. 1B,C)
Summary
Restoring neuronal connections and function in degenerative diseases and after injury in the CNS is a critical goal for neuroscience and has been investigated for decades, with only a handful of approaches showing promiseReceived August 16, 2020; accepted December 22, 2020; First published January 13, 2021. Restoring neuronal connections and function in degenerative diseases and after injury in the CNS is a critical goal for neuroscience and has been investigated for decades, with only a handful of approaches showing promise. January/February 2021, 8(1) ENEURO.0358-20.2020 1–8 in preclinical models. Retinal ganglion cells (RGCs), projection neurons responsible for transmitting vision from the eye to the brain, have been a major target for research as RGCs undergo cell death and axon. Research Article: Confirmation 2 of 8 degeneration in patients suffering from glaucoma or other optic neuropathies (Goldberg et al, 2016). Optic nerve models are relevant for studying CNS axon regeneration and have pointed to a number of discoveries of signaling pathways implicated in survival and axon regeneration (Benowitz et al, 2017)
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