Intrinsic transcriptional programs for regeneration of serotonergicconnectivity - Permanent disabilities following axonal injuries result from the failure of injured axons to regenerate and rebuild functional connections. Controlling axon regeneration is highly relevant to the development of therapeutic strategies for nervous system repair. Most axons in the adult mammalian central nervous system (CNS) fail to regenerate after injury, whereas axons in the peripheral nervous system (PNS) can regenerate. Interestingly, serotonin (5-HT) neurons in the CNS have an atypical capacity for axonal regrowth after injury. However, the intrinsic molecular mechanisms underlying 5-HT axon regeneration are not understood. It seems likely that elucidating these mechanisms will help to explain why 5-HT neurons are exceptional in the ability to regenerate connectivity. Recently, we showed that two transcription factors, Lmx1b and Pet1, control a 5-HT axonal growth program during a development and an axonal maintenance program in adult 5-HT neurons. These findings led me to hypothesize that Lmx1b and Pet1 may also be required to control a distinct intrinsic axonal regeneration program in injured adult 5-HT neurons. Interestingly, my preliminary in vivo results showed that adult-stage Lmx1b and Pet1 deficiency inhibits serotonergic regeneration. Thus, in this proposal I will investigate the following broad question: Do Lmx1b and Pet1 control a distinct axonal regeneration transcriptional program? To address this question, I will (1) investigate adult-stage Lmx1b and Pet1 function in the regeneration of 5-HT axons and synapses, (2) investigate the transcriptomic and chromatin mechanisms underlying 5-HT axon regeneration, and (3) investigate Lmx1b and Pet1 function in the regulation of an adult- stage 5-HT regeneration program. My long-term goal is to understand the mechanisms that can enable axons regenerate after injury and use the insights to develop therapeutic strategies. 5-HT neurons provide a unique opportunity to investigate the intrinsic mechanisms that enable axonal regrowth after injury. As my primary expertise is in Biochemistry and Genetics, my proposal studies bring me significant changes from my previous expertise and enable me to break into a new field of study, and acquire new techniques, including bioinformatical analyses, neuroimaging techniques, modified genetic tools, and behavior analysis. My career goal is to appropriately combine these techniques and scientific insights acquired though this K01 to clarify mechanisms underlying 5-HT axon regeneration, building a scientific career as an established researcher.
