THE ROLE OF NRG1-ERBB2 PATHWAY IN PROMOTING SPINAL CORD REGENERATION IN THE AXOLOTL

Background: The axolotl (Ambystoma mexicanum) is one of the only known tetrapod vertebrates capable of full spinal cord regeneration. In mammals, however, similar injury is completely debilitating, as it permanently forms a glial scar, which prevents regeneration. Therefore, the axolotl is an indispensable model for the study of the molecular pathways underlying regenerative abilities. This work focuses on discovering the functional role of Neuregulin 1 (NRG1) during adult neurogenesis and spinal cord regeneration after injury. Neuregulin 1 is a growth factor particularly important to the nervous system. NRG1 signaling is associated with the promotion of remyelination and functional recovery after nerve injury, and the loss of this signaling has been shown to lead to schizophrenia and epilepsy. We hypothesize that Neuregulin 1 signaling promotes spinal cord regeneration by increasing neurogenesis and cell survival. Methods: We have tested our hypothesis by localizing and characterizing NRG1 positive cells in the spinal cord of injured and uninjured animals using IHC. We have pharmacologically inhibited NRG1 signaling using Mubritinib. We have also performed electroporation of gene constructs into the central canal of axolotl spinal cord to elucidate NRG1 function during axolotl spinal cord regeneration. Results: We have shown that pharmacological inhibition of NRG1 signaling prevents axolotl tail and spinal cord regeneration. Animals treated with the NRG1 receptor inhibitor Mubritinib did not fully regenerate their tails and had structurally abnormal spinal cord compared to control animals, which could be due to reduced neurogenesis exhibited after drug-treatment. The importance of NRG1 for neurogenesis is also highlighted by the fact that NRG1 positive cells are lining the stem cell niche of the spinal cord in a healthy animal. Conclusion: Overall, our preliminary results highlight the crucial role of NRG1-ErbB2 signaling pathway in promoting spinal cord regeneration in the axolotl by increasing neurogenesis.