Although adult neurons in the mammalian central nervous system (CNS) cannot spontaneously repair themselves after injury, a growing body of evidence indicates that genetically manipulating them can increase their intrinsic reparative ability. However, as genetic manipulation is not clinically feasible, current research continues to investigate pharmacological approaches to transiently enhance the intrinsic ability of adult CNS neurons to survive and regenerate their axons. Amphiregulin (AREG) is a unique epidermal growth factor receptor (EGFR) ligand that has been shown to be crucial in liver regeneration, and accumulating evidence suggests that AREG signaling can promote both survival and axon regeneration of neurons. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β (TGF-β) superfamily, and it has been shown to exert rejuvenation effects in the aged brain and promote neuronal survival in the CNS. However, it is unknown whether AREG and GDF11 are capable of inducing neuronal survival and axon regeneration in the visual system. Hence, the current study investigated: 1) the developmental and post-injury expression patterns of these two ligands and their respective receptors, EGFR and activin-like kinase 5 (ALK5), 2) the potential neuroprotective and regenerative effects of these two ligands on retinal ganglion cells (RGCs) by using optic nerve crush (ONC) model, and 3) the molecular mechanisms mediating the neuroprotective and regenerative effects of AREG and GDF11 on RGCs. Based on the western blot and immunohistochemical data, both AREG and GDF11 are consistently expressed throughout retina development, but their receptors are only upregulated during early retina development. Furthermore, AREG expression is significantly reduced in adult retina 7 days after ONC whereas GDF11 expression remains unchanged after ONC. Interestingly, while EGFR expression is only upregulated 3 days after ONC, ALK5 expression is consistently upregulated throughout the ii post-injury time course. A single intravitreal injection of AREG or GDF11 immediately after ONC promoted significant RGC survival by activating Smad2/3 pathway. Because both ligands were not able to promote RGC axon regeneration, activation of Smad2/3 pathway may promote RGC survival but suppress RGC axon regeneration. Overall, the findings indicate that both AREG and GDF11 hold therapeutic potential for both neurodegenerative diseases and retinal degenerative diseases.iii Acknowledgement I am not supposed to be where I am today. Growing up in South Korea, I was told by teachers and tutors that I am intellectually challenged, and I have no gift for science.Naturally, I never thought that I would become a scientist, and yet here I am. First and foremost, I would like to sincerely thank my graduate supervisor Dr. Patrice Smith for allowing me to join her lab and always finding time to provide guidance and encouragement during my PhD despite her super-duper busy schedule. I learned so much from you over the years, and I would not be...