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A research team from the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has discovered an unprecedented molecular mechanism to govern the formation of sensory neurons versus satellite glial cells in the dorsal root ganglia. The discovery provided insight into the pathological changes in pain development that paves the way for new therapeutic opportunities.

In our peripheral nervous system, sensory neurons and their surrounding satellite glial cells in the dorsal root ganglia (or spinal ganglia) are responsible for transmitting external stimuli such as temperature, touch and pain to the central nervous system. Therefore, generation of the correct numbers of sensory neurons and satellite glial cells are essential for the proper functioning of our sensation. Disrupting the balance of forming these cell types could result in various pain disorders such as allodynia or analgesia. However, the molecular mechanism underlying the cell fate choice to generate sensory neurons versus satellite glial cells is not clear to date.

The new findings are the concerted efforts of research teams from the School of Biomedical Sciences and Laboratory and Clinical Research Institute for Pain, the Department of Anaesthesiology, HKUMed. The findings are published in Proceedings of the National Academy of Sciences of the United States of America (link to the publication).

Background
Both sensory neurons and satellite glial cells are originated from a multipotent population of neural crest progenitors which detach from the dorsal neural tube and undergo migration to the periphery where they give rise to the peripheral nervous system including sensory nervous system. Previous studies showed that Sox10, a member of SOXE transcription factor family and the proneural basic-helix-loop-helix transcription factor, Neurogenin 2 (Neurog2) are initially co-expressed in neural crest progenitors, which eventually give rise to two distinct cell types: Sox10 satellite glial cells and Neurog2 sensory neurons in the dorsal root ganglia, but the molecular mechanism of how this process occurs is not well understood.

Research methodology and findings
Since the development of nervous system in early chick embryos is very similar to human, the research team used chick embryos as the model organism to study how neural crest progenitors give rise to sensory neurons and satellite glial cells. The team used the technique called in ovo electroporation to increase Sox10 expression level in neural crest progenitors followed by RNA sequencing to examine global gene expression change in the sensory nervous system. Based on this analysis, the team identified Fbxo9, a member of the F-box protein family as a downstream target of Sox10 involved in the breakdown of Neurog2 protein that determine the formation of satellite glial cells. Consistently, inhibition of Fbxo9 function resulted in accumulation of Neurog2 protein which prevented the formation of satellite glial cells. In contrast, overexpression of Fbxo9 promoted the degradation of Neurog2 protein that led to the reduction in the number sensory neurons formation.

Altogether, the findings revealed a new mechanism in which Sox10 activates Fbxo9 expression to destabilize Neurog2 protein leading to differentiation of neural crest progenitors into satellite glial cells but not sensory neurons in the dorsal root ganglia.

Significance of the study
“Our findings provide in vivo evidence for the first time that a satellite glial cell regulator Sox10 inhibits sensory neurons formation via a protein breakdown mechanism. The research team identified Fbxo9 as a key downstream effector of Sox10 to mediate the breakdown of sensory neuron regulator Neurog2 protein that resulted in directing neural crest progenitors to differentiate into satellite glial cells but not sensory neurons in the forming dorsal root ganglia. Our results could have broader implications that protein degradation process may represent an alternative strategy to control cell fate decision in other tissue development,” said Dr Martin Cheung Chi-hang, Associate Professor, the School of Biomedical Sciences, HKUMed and also the lead researcher of the study.

“Recent studies showed that satellite glial cells play an important role in neuropathic pain. Understanding the molecular control of satellite glial cells formation will provide insight into the pathological changes in pain development that pave the way for therapeutic opportunities,” said Dr Jessica Liu Aijia, Research Assistant Professor, the Department of Anaesthsiology, and Deputy Director of the Laboratory and Clinical Research Institute for Pain, HKUMed and also the lead author of the publication.

About the research team
The research was led by Dr Martin Cheung Chi-hang, Associate Professor of the School of Biomedical Sciences, HKUMed. He has long-term research interests in elucidating the genetic regulation of multipotent neural crest formation, migration and differentiation in order to provide molecular insights into how neural crest cells give rise to metastasis melanoma. Dr Jessica Liu Aijia, Research Assistant Professor of the Department of Anaesthesiology and Deputy Director of the Laboratory and Clinical Research Institute for Pain, HKUMed is the lead author of the publication. Her research interests focus on the genetic regulation of the nervous system development and the mechanisms of pathological pain. Other HKU scientists contributing to the research included Dr Andrew Tai Chi-pang, Senior Technical Officer of the Department of Medicine, Ms May Cheung Pui-lai, Senior Technician of the School of Biomedical Sciences in Dr Martin Cheung’s lab and Mr Hong Jialin, MBBS Year 2 student, HKUMed.

Key collaborators include Professor Kathryn Cheah Song-eng, Jimmy and Emily Tang Professor in Molecular Genetics and Chair Professor of Biochemistry of the School of Biomedical Sciences, HKUMed, Professor Sham Mai-har of the School of Biomedical Sciences, HKUMed and Professor Cheung Chi-wai, Clinical Professor of the Department of Anaesthesiology and Director of the Laboratory and Clinical Research Institute for Pain, HKUMed.

Acknowledgements
The work was supported by grants from the Research Grants Council and University Grants Committee, Hong Kong (M.C.: GRF_17110715, GRF_17123016 and KC: AoE/M-04/04, T12C-714/14-R, T12-708/12N).

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medkefa@hku.hk).