Abstract
Purpose: The present study examines the role of Sox11 in the initial response of retinal ganglion cells (RGCs) to axon damage and in optic nerve regeneration in mouse.Methods: Markers of retinal injury were identified using the normal retina database and optic nerve crush (ONC) database on GeneNetwork2 (www.genenetwork.org). One gene, Sox11, was highly upregulated following ONC. We examined the role of this transcription factor, Sox11, following ONC and optic nerve regeneration in mice. In situ hybridization was performed using the Affymetrix 2-plex Quantigene View RNA In Situ Hybridization Tissue Assay System. Sox11 was partially knocked out by intravitreal injection of AAV2-CMV-Cre-GFP in Sox11f/f mice. Optic nerve regeneration model used Pten knockdown. Mice were perfused and the retinas and optic nerves were dissected and examined for RGC survival and axon growth.Results: Sox11 was dramatically upregulated in the retina following ONC injury. The level of Sox11 message increased by approximately eightfold 2 days after ONC. In situ hybridization demonstrated low-level Sox11 message in RGCs and cells in the inner nuclear layer in the normal retina as well as a profound increase in Sox11 message within the ganglion cells following ONC. In Sox11f/f retinas, partially knocking out Sox11 significantly increased RGC survival after ONC as compared to the AAV2-CMV-GFP control group; however, it had little effect on the ability of axon regeneration. Combinatorial downregulation of both Sox11 and Pten resulted in a significant increase in RGC survival as compared to Pten knockdown only. When Pten was knocked down there was a remarkable increase in the number and the length of regenerating axons. Partially knocking out Sox11 in combination with Pten deletion resulted in a fewer regenerating axons.Conclusion: Taken together, these data demonstrate that Sox11 is involved in the initial response of the retina to injury, playing a role in the early attempts of axon regeneration and neuronal survival. Downregulation of Sox11 aids in RGC survival following injury of optic nerve axons, while a partial knockout of Sox11 negates the axon regeneration stimulated by Pten knockdown.
Highlights
Advances in our ability to monitor molecular changes in neurons have led to an increased understanding of the events that transpire following neuronal injury (Howell et al, 2011; Moore and Goldberg, 2011; Vazquez-Chona and Geisert, 2012; Munguba et al, 2013; Templeton et al, 2013)
To define the changes in Sox11 that occur following injury to the optic nerve, we compared Sox11 mRNA levels in normal mice to Sox11 levels following optic nerve crush (ONC) using the bioinformatic tools on GeneNetwork1
The C57BL/6 strain had an expression level of 11.33 after ONC and the expression in the DBA/2J strain increased to 11.44. These data indicate that Sox11 is dramatically upregulated after a specific injury to the ganglion cell axons within the optic nerve
Summary
Advances in our ability to monitor molecular changes in neurons have led to an increased understanding of the events that transpire following neuronal injury (Howell et al, 2011; Moore and Goldberg, 2011; Vazquez-Chona and Geisert, 2012; Munguba et al, 2013; Templeton et al, 2013). The initial response of a central nervous system (CNS) neuron may be similar to that of a neuron in the peripheral nervous system (PNS) (Carlstedt, 1997). When examining the initial response of neurons to injury, there are some common responses in the CNS and PNS. One transcription factor activated in both the CNS and PNS after injury is Sox (McCurley and Callard, 2010; Struebing et al, 2017). There is strong evidence that this gene is part of the transcriptional network activated by injury and involved in axonal regeneration in the PNS (Jankowski et al, 2009; Jing et al, 2012)
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