Summary: Findings could pave the way for developing new treatments to restore vision and repair retinal damage.
Source: Brigham and Women’s Hospital.
Untangling the complex puzzle of optic nerve regeneration.
The optic nerve is vital for vision — damage to this critical structure can lead to severe and irreversible loss of vision. Fengfeng Bei, PhD, a principal investigator in the Department of Neurosurgery at Brigham and Women’s Hospital, and his colleagues want to understand why the optic nerve — as well as other parts of the central nervous system including the brain and spinal cord — cannot be repaired by the body. In particular, Bei’s lab focuses on axons, the long processes of neurons that serve as signaling wires. In a new study published in Neuron, Bei, Michael Norsworthy in Zhigang He’s lab at Boston Children’s Hospital and colleagues report on a transcription factor that they have found that can help certain neurons regenerate, while simultaneously killing others. Unraveling exactly which signals can help or hinder axon regeneration may eventually lead to new and precise treatment strategies for restoring vision or repairing injury.
“Our long term goal is to repair brain, spinal cord or eye injury by regenerating functional connections,” said Bei. “The goal will be to regenerate as many subtypes of neurons as possible. Our results here suggest that different subtypes of neurons may respond differently to the same factors. This may mean that when we reach the point of developing new therapies, we may need to consider combination therapies for optimal recovery.”
Previous studies using the optic nerve as a model for injury have found that manipulating transcription factors — the master control switches of genes – might represent a promising avenue for stimulating axon regeneration. In the current study, researchers focused on transcription factors likely to influence the early development of retinal ganglion cells (RGCs). There are at least 30 types of RGCs in the human eye, which control different aspects of vision, and the researchers were interested in the effects of transcription factors on various types of RGCs. Using a mouse model of optic nerve injury, the research team found that increasing the production of a transcription factor known as Sox11 appeared to help axons grow past the site of injury. However, the team observed that the very same transcription factor also efficiently killed a type of RGCs known as alpha-RGCs which would preferentially survive the injury if untreated.
Bei notes that the heterogeneity of the nervous system — the inclusion of different cells with different properties and functions — will be an important consideration as researchers work to reprogram and, ultimately, restore the optic nerve, brain or spinal cord after injury.
Bei is a co-first and co-senior author of this study. Two other senior authors are Zhigang He, PhD, BM, at Boston Children’s Hospital and Giovanni Coppola, MD, at University of California, Los Angeles
Funding: Funding provided by National Institutes of Health, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Source: Haley Bridger – Brigham and Women’s Hospital
Image Source: NeuroscienceNews.com image is credited to Fengfeng Bei, Brigham and Women’s Hospital.
Original Research: Abstract for “Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others” by Michael W. Norsworthy, Fengfeng Bei, Riki Kawaguchi, Qing Wang, Nicholas M. Tran, Yi Li, Benedikt Brommer, Yiming Zhang, Chen Wang, Joshua R. Sanes, Giovanni Coppola, and Zhigang He in Neuron. Published online June 21 2017 doi:10.1016/j.neuron.2017.05.035
Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others
•Sox11 promotes robust axon regeneration from injured adult RGCs
•Sox11 re-activates a developmental axon growth program
•Sox11 kills α-RGCs and promotes regeneration from other types
•Pten deletion enhances axon regeneration induced by Sox11 expression
At least 30 types of retinal ganglion cells (RGCs) 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 overexpressing 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, α-RGCs, which preferentially regenerate following treatments such as Pten deletion, were killed by Sox11 overexpression. Thus, Sox11 promotes regeneration of non-α-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.
“Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others” by Michael W. Norsworthy, Fengfeng Bei, Riki Kawaguchi, Qing Wang, Nicholas M. Tran, Yi Li, Benedikt Brommer, Yiming Zhang, Chen Wang, Joshua R. Sanes, Giovanni Coppola, and Zhigang He in Neuron. Published online June 21 2017 doi:10.1016/j.neuron.2017.05.035