Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others

Abstract

SUMMARY At least 30 types of retinal ganglion cell (RGC) send distinct messages through the optic nerve to the brain. Available strategies of promoting axon regeneration act on only some of these types. Here we tested the hypothesis that over-expressing developmentally important transcription factors in adult RGCs could reprogram them to a “youthful” growth-competent state and promote regeneration of other types. From a screen of transcription factors, we identified Sox11 as one that could induce substantial axon regeneration. Transcriptome profiling indicated that Sox11 activates genes involved in cytoskeletal remodeling and axon growth. Remarkably, alpha-RGCs, which preferentially regenerate following treatments such as PTEN deletion, were killed by Sox 11 overexpression. Thus, Sox 11 promotes regeneration of non-alpha RGCs, which are refractory to PTEN deletion-induced regeneration. We conclude that Sox11 can reprogram adult RGCs to a growth-competent state, suggesting that different growth-promoting interventions promote regeneration in distinct neuronal types.

Intrinsic mechanisms of neuronal axon regeneration

“…For example, it was recently shown that SOX11, a known pro-regenerative transcription factor in the PNS 139 , can reprogramme adult non-α-RGCs to a growth-competent state. By contrast, SOX11 expression kills α-RGCs, the cellular subtype that preferentially regenerates following treatments such as PTEN deletion 143 . SOX11 expression also promotes CST regeneration after spinal cord injury but interferes with functional recovery 142 .…”

“…In addition to the previously highlighted transcription factors, several others — namely Myc proto-oncogene protein (MYC) 137 , hypoxia-inducible factor 1α (HIF1α) 138 , CREB1 (REFS 36,113 ), SOX11 (REFS 139–143 ), TP53 (REFS 46,144 ), SRF48,145 and XBP1 (REFS 90,91 ) — have been identified to have roles in axon regeneration (see TABLE 1 and REFS 146,147 ). As little is known about the mechanisms by which these transcription factors are activated after injury, their regulation during development or their downstream targets, they will not be further discussed in detail here.…”

“…Genetic manipulations that have focused on overexpression of regeneration-associated genes or transcription factors have yielded limited success 114,143,146,148 . This lack of success could be because more than one factor is necessary to fully stimulate the growth process; however, another explanation is that the cellular context dictates the competency of the neurons to respond to a given genetic manipulation.…”

“…In the context of cellular reprogramming, the accessibility of the chromatin to a given transcription factor dictates the effectiveness of the conversion 227 . Differences in chromatin accessibility may also lead to different outcomes, as genomic regions that are differentially bound by given transcription factors or differences in signalling pathways may lead to different cellular responses, such as the cell death and regeneration that are promoted by transcription factor SOX11 (REF 143 ) and dual leucine zipper bearing kinase (DLK) 65 , respectively. As such, therapies that address both cellular competency and the manipulation of gene expression may be necessary.…”

A single factor induces neuronal differentiation to suppress glioma cell growth

“…Sox11 can reprogram adult optic ganglion cells to a state with sufficient growth capacity, thereby promoting the regeneration of certain types of optic ganglion neurons . NEUROG2 and SOX11 synergistically convert human glioma cells into terminally differentiated neuron‐like cells in vitro and in adult mouse brain .…”