Mechanics of scale regeneration induced by Erk activity waves
Description: During regeneration, signaling molecules direct patterned growth allowing adult tissues to regain their original morphological and functional characteristics after damage. How cell signaling orchestrates proper growth and morphogenesis of large adult appendages over long time periods is poorly understood. In recent years, mechanical forces have emerged as key regulators of tissue size and shape during embryonic organ formation. However, how mechanics influence growth and morphogenesis of regenerating body parts remains unclear and largely unexplored. In this project, I will address these questions using zebrafish scales, which are exoskeletal dermal bones that fully restore their initial size and shape two weeks after loss and are readily compatible with quantitative live imaging. Scale regeneration proceeds through phases of differentiation, proliferation and hypertrophic growth. In the hypertrophic phase, tissue growth is coordinated by concentric waves of Erk activity, dependent on Fgf signaling. Five to six waves are produced throughout scale regeneration, with each expanding wave traversing the tissue to stimulate localized cell growth. What is the impact of Erk mediated wave-patterned cell growth to the scale morphogenesis during regeneration is poorly understdood. Thus, in this project I will focus on describing the mechanical forces arising from waved patterned growth and their impact in scale morphogenesis. First, I will develop a quantitative framework to measure osteoblasts mechanical properties and the tissue-wide mechanical stresses associated to Erk activity in waves. I will perform high-resolution live imaging to capture the change in osteoblast size and shape over time, and laser ablations at the cell and tissue levels. The quantitative analysis of these approaches will generate the force landscape of regenerating scales resulting from wave-patterned growth. Subsequently, I aim to understand how the mechanical stresses related to Erk wave-induced growth lead to proper scale morphogenesis. To do so, we will develop a theoretical model of scale growth to identify which aspects of Erk signaling dynamics and the tissue mechanics determine the final scale size and shape during regeneration. Based on the model predictions, I will genetically or pharmacologically alter the distribution of forces in the scale by perturbing the properties of Erk signaling waves and will evaluate the effect of the perturbations in the final size and shape of regenerating scales. In this aim by combining physics and experimental biology, I will connect the pattern of forces associated to Erk activity in waves to the scale morphogenesis. Finally, I will examine the effects of induced mechanicall stresses on the generation and propagation of Erk activity waves. To do so, I will manipulate genetically and pharmacologically the actomyosin network dynamics and will stablish a scale explant culture to directly manipulate scale forces. Then, I will evaluate the impact of these perturbations on the generation, speed, and frequency of Erk waves, as well as on scale morphology. These experiments will elucidate if feedback between mechanics and Erk signaling takes place during regeneration to regulate scale morphogenesis. Altogether, the results of this interdisciplinary project will shed light on the understanding of how local cellular growth is integrated tissue-wide to regulate organ size and shape. This is particularly relevant in the context of regeneration, in which tissues are large, grow fast and are constrained by the cellular environment of adult animals. This project will also provide novel insights on the role of mechanical forces on bone morphogenesis. The insights gained from this study could be relevant to the field of bone regeneration as well as to research in other organs that are exposed to injury, such as the spinal cord or limbs.
Amount: CHF 234,200
Funding type: fellowship
Funder scheme: SNSF Swiss Postdoctoral Fellowships
Start date: 2025-01-01
End date: 2026-12-31
Investigator: Bocanegra-Moreno, Laura
Institution: University of Geneva – GE
Funded outputs count: 0
Funder award ID: 224303
OpenAlex ID: G2012533555