Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Dr. Arthur Brown

Abstract

This thesis investigates the effect of Sox9 knockdown on anti-regenerative scar gene expression, neuroplasticity, and hind limb functional recovery following mouse spinal cord injury. We hypothesized that Sox9 knockdown would reduce expression of anti-regenerative chondroitin sulfate proteoglycans both at the lesion site and at sites distant to the injury, thus providing an avenue for increased neuroplasticity and locomotor recovery after spinal cord injury. The first chapter provides a general introduction to the biological problem of spinal cord injury. The development of the glial scar and expression of the anti-regenerative chondroitin sulfate proteoglycan extracellular matrix is introduced, and Sox9 is identified as a transcription factor that may control expression of these anti-regenerative genes. The second chapter is a manuscript that describes the molecular changes and improved locomotor function seen when Sox9 knockdown is carried out just prior to spinal cord injury. The third chapter is more clinically relevant as it is a manuscript detailing the effects of Sox9 knockdown after spinal cord injury on the recovery of hind limb motor function. The fourth chapter is a manuscript investigating the neuro-anatomical mechanism of the improved functional recovery seen in Sox9 knockdown mice after spinal cord injury. The fifth chapter reflects on the findings presented herein, and suggests possible future plans of study. This dissertation demonstrates that inhibition of Sox9 leads to reduced CSPG expression, improved hind limb function, and increased total locomotion. It further provides compelling evidence that increased neuroplasticity as evidenced by increased reactive sprouting and increased expression of the presynaptic markers synaptophysin and VGLUT1 caudal to the injury site underlies the improved neurological recovery observed in spinal cord injured Sox9 conditional knockdown mice.


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