Signal scaling during limb regeneration of different sized animals
Final Report Abstract
Unlike humans, some animals including axolotls can regrow lost limbs. How large animals regrow lost limbs, and in particular how the size of the regenerating body part is matched to the often widely varying size of adult animals is not well understood. We investigated this open problem of adaptive morphogenesis in the remarkable axolotl, where regenerating blastemas (wound tissue) can vary more than three-fold in linear dimensions depending on animal size. We combined experimental quantification of morphogen gradients in 3D and mathematical modeling, to identify potential mechanisms of growth control. It is established that a system of oppositely-oriented morphogen gradients (SHH & FGF8) controls growth, yet not how this system (i) responds to tissue size and (ii) controls tissue size. On the theory side, we systematically formulated possible models of growth control by oppositely-oriented morphogen gradients and analyzed these mathematical models for their ability to enable robust growth arrest and proportional growth. This theoretical analysis substantially reduced a range of hypothetical mechanisms. We conclude and propose that at least one morphogen source size should scale proportionally with animal size, but then remain static during blastemal growth. On the experimental side, this is indeed what we observed by quantifying morphogen gradient parameters using in-situ hybridization at different time-points of regeneration. Based on our findings, we propose a simple, yet effective mechanism for robust growth arrest, where two overlapping morphogen gradients jointly promote t issue growth, which subsequently decreases the overlap between both gradients and eventually halts morphogen signaling and arrests tissue growth. We expect that the simple and robust growth control mechanism put forward here may apply to limb development and regeneration also in other species.
Publications
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Static morphogen scaling enables proportional growth in a tissue growth model inspired by axolotl limb regeneration. Proceedings of the National Academy of Sciences, 122(47).
Lyubaykina, Natalia; Knapp, Dunja; Tardivo, Pietro; Kotz, Maximilian; Sandoval-Guzmán, Tatiana & Friedrich, Benjamin M.
