F31 Microtubule function in the onset of whole-body regeneration

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Project Summary Tissue regeneration is the process of renewal, restoration and growth that allows an organism to re-grow limbs and organs after injury. Tissue regeneration abilities are present in diverse organisms, suggesting they may have been ancient, so the mechanisms controlling regeneration have been important to understand. The freshwater planarian flatworm Schmidtea mediterranea regenerates from nearly any surgical injury, including decapitation, and is a model for understanding the mechanistic basis of animal regeneration. After injury, tissue near wound sites signals to nearby adult pluripotent stem cells called neoblasts, which differentiate to replace all cell types of missing tissue. The highly conserved Wnt signaling pathway is essential for controlling regeneration of anterior-versus-posterior tissue identity in planarian regeneration. The earliest event in head versus tail determination is the injury induced expression of the secreted Wnt inhibitor notum selectively at anterior-facing and not posterior-facing wound sites. However, the mechanism directing this symmetry breaking event is unknown. Injury induced notum expression occurs from the soma of body wall muscle cells possessing longitudinally aligned muscle fibers, suggesting a role of muscle cell orientation and polarity in the onset of regeneration. However, the molecular signals and structure regulating this polarity are unknown, but classic small molecule inhibition studies in planaria suggest a possible role for microtubules in this process. The goal of this project is to uncover the mechanisms by which microtubules participate in the polarity of the regeneration response in the following specific aims. Aim 1 utilizes RNAi to test roles for microtubule regulatory factors expressed in muscle to control injury-induced gene expression at the onset of tissue regeneration. Aim 2 uses epistasis analysis with RNAi to uncover the mechanism by which a kinesin microtubule motor protein relates to a Wnt pathway for head and eye regionalization used in regeneration. These experiments will provide insight on the cellular and molecular mechanism of microtubules during injury induced regeneration. My results will provide new insights into understanding the other factors necessary for proper injury signal and help form a better understanding on what regulates polarity.