Understanding Spinal Cord Regeneration; the role of dynamic gene expression

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Animals at embryonic stages are capable of reconstructing functional tissue after disruptive injuries. Extensive research in the field of regenerative medicine aims to understand the similarities between embryogenesis and regeneration programs and despite great advances in the last few decades, many aspects of the biological and molecular mechanisms remain unknown. Mammals, including humans, cannot replace lost neurons after spinal cord injury (SCI), whereas zebrafish can regenerate neurons to replace those that are lost after injury. Upon injury, neural stem cells initiate proliferation and generate new neurons in species with regenerative capacity, but in mammals, only cells that contribute to scar formation are generated. My own research has shown that during development the generation of new neurons (neurogenesis), genes are not simply on or off. Instead, the levels of some genes pulse dynamically over time, influenced by specific factors, and control whether the cells decide to stay as proliferating neural stem cell or become new neurons. It is known that the same genes are important during spinal cord regeneration (SCR) but how they work isn't known. Therefore, it is not clear whether during SCR and the generation of new neurons are also controlled by the pulses in gene activity. Elucidating the dynamic signals and mechanisms leading to successful SCR in an animal with regenerative capacity will generate important and valuable outcomes that can be tested in higher organisms. Zebrafish is a powerful, tractable and robust animal model able to achieve functional neural regeneration following SCI, characterised by de novo neurogenesis and regrowth of neuronal connections. In this proposal I will be using larvae zebrafish as an experimental model, taking advantage of its regenerative capacity and its amenability to genetic manipulation. I will use state-of-the art live imaging techniques that show gene activity in real time. I will introduce genetic changes to assess the functional importance of pulsatile gene activity when neural stem cells undertake neuronal decisions during SCR. I will investigate how changes on pulsatile gene activity can affect the genetic landscape and alter cell-fate decisions over time during SCR. Addressing the functional importance of pulsatile gene activity during cell-fate decisions in SCR, will provide insights with potential translational implications for SCI in animals with no regenerative capacity, such as mice and humans.