Quantitative dissection of the events that encode bone size and shape during regeneration

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ABSTRACT Mammals possess a limited compacity to regenerate appendages following traumatic injury and amputation, including regenerating digit tips and healing of bone fractures. In contrast, zebrafish can regenerate entire appendages following amputation. As in development, regenerated appendages are scaled appropriately to body size. Extensive genetic and pharmacological experiments have established that canonical signaling pathways, such as Fgf and Wnt, are reactivated following injury to promote the cell proliferation, migration, and differentiation that drives regeneration of appendages. However, how these pathways encode size and shape is unclear. This is due, in part, to the limited number of quantitative and dynamic descriptions of these signaling pathways and their downstream cellular events during regeneration. To address these gaps in the understanding of appendage scaling during regeneration, this proposal aims to develop a quantitative, live imaging platform for zebrafish caudal fin regeneration. Specifically, Aim 1 will determine the role of extracellular signal-regulated kinase (ERK) in encoding cell proliferation and bone size during fin ray regeneration. Aim 2 will define the role of negative feedback during fin regeneration and investigate whether this negative feedback contributes to the robustness of this regeneration event. Collectively, this work will establish a quantitative model for interrogating the cellular basis of size and shape control during regeneration. This work will be conducted at Duke University under the mentorship of Dr. Di Talia and Dr. Poss. This is a highly collaborative training environment that affords expertise in quantitative and regenerative biology. This proposed research will be carried out alongside focused training in quantitative approaches, scientific writing, and mentorship.