Characterizing genes that regulate dopaminergic neuron regeneration in the planarian brain

Project summary Despite decades of research uncovering the basis of neurogenesis during development, we do not know as much about neurogenesis in a regenerative context. Regeneration, or the ability to regrow lost tissue, is a rare feat in the animal kingdom. Although humans can replenish few cell types in the adult brain, they do not have the ability to regrow large sections of tissue after injury. Improved regenerative therapies would benefit patients who have experienced stroke, neurodegenerative disease, or traumatic injury. Because the human brain regenerates itself poorly, our lab seeks to explore fundamental principles of successful brain regeneration using organisms that can regenerate – planarians. Planarian flatworms regenerate all their body structures, including a brain, over the course of a week. However, we currently understand little about the genetic mechanisms governing neural regeneration in planarians. To uncover mechanisms of brain regeneration, this proposal focuses on elucidating the timeline of dopaminergic neuron maturation and characterizing genes important for dopaminergic neuron regeneration. A preliminary screen revealed two genes important for regeneration of dopaminergic neurons in the planarian brain, lim only domain 3 (lmo3) and amyloid precursor protein. To further study roles of these genes, I will perform the research outlined in this proposal. Aim 1: I will establish a timeline of dopaminergic neuron maturation and regeneration. Aim 2: I will uncover the cellular mechanism through which LMO3 promotes neuron regeneration. Aim 3: I will characterize the molecular mechanism by which LMO3 impacts dopaminergic regeneration in the planarian brain. My studies will improve our fundamental knowledge of planarian neural regeneration, outlining a path for elucidating the full genetic mechanism behind creation of dopaminergic neurons from pluripotent stem cells in this fascinating organism. My data will also establish a protocol for characterizing cellular lifespan and will create new protocols for discovering new protein-protein interactions in planarians. The fundamental scientific knowledge gleaned from the completed aims will reveal how successful regeneration of specific cell types is accomplished over time. Future applications of this work could inform preclinical treatments for neurodegenerative disorders, contributing to the promise and possibility of successful brain regeneration.