Physical principles of tissue size control in zebrafish scale regeneration
Description: Background. Regeneration is the spectacular process in which a lost body part regrows to its original form. While mammals have limited regeneration capabilities, fish can regenerate several organs and appendages, including fins and scales. Regeneration poses fundamental questions regarding how chemical and mechanical signals act to recover a tissue of the right size, shape and pattern, starting from variable injuries. In particular, several chemical factors important for regeneration have been discovered in the past, but it is unclear how they are organized in time and space to coordinate regeneration. For example, the large spatial dimensions of regenerating tissues challenge classic models of organ size control, such as the diffusible morphogen gradient model. I believe that tackling the mechanisms of regeneration requires a quantitative approach. Specifically, it requires combining a tractable system with live imaging and measurements, ideally in their native context. Mathematical modelling is fundamental to conceptualize the interplay of signals and cell behaviours, generate hypothesis and guide quantitative data analysis. During my postdoc, I developed a quantitative platform to study the signals coordinating regeneration in the zebrafish scales, a simple system amenable to live imaging. Scales are bone disk, in which the bone matrix is deposited by a mono-layer of quickly regenerating osteoblasts. I discovered that the regeneration of the osteoblast tissue is coordinated by a train of Erk activity waves. Erk activity waves originate from a central source and propagate as expanding rings. Erk activity waves impart patterned osteoblast hypertrophy and thus coordinate scale growth. We propose excitable waves as a new mode of coordination of regenerative growth in large tissues. Objectives. I will leverage on my quantitative platform, using scales as a model system, to ask how Erk dynamics, integrated with other mechanical and chemical signals, determine the final number of cells, size, shape and maturation of a bone tissue. Then, I will extend this program to the study of tissue interactions and to the morphogenesis of more complex body parts. I expect that these methods and concepts developed in scales will be applicable in several contexts and species.Significance. My research program will bridge biological events at different spatial and temporal scales, from cell signalling to tissue morphogenesis, to understand the mechanisms of regeneration. We will apply a highly interdisciplinary approach employing concepts and techniques from cell biology, development, computer science and physics. I anticipate that our results will be of great interest to a broad scientific community and contribute to establishing the emerging field of quantitative regeneration. My work will contribute to the understanding of the fundamental mechanisms underlying multi-cellularity and how they are harnessed in regeneration for proper morphogenesis. I surmise that our results will be important for improving our understanding of tissue health and potentially guide future explorations in regenerative medicine.Specific Aims. My research proposal is organized in two Aims targeted at addressing the control of scale tissue size and number of cells. I also describe further directions that I will address funded by independent sources. • Aim 1. We will investigate how Erk activity wave generation is tuned during scale regeneration to control tissue size. We will ask what feedback mechanisms informs the wave source on tissue size to stop wave generation as scales reach their final form. To address these questions, we will correlate Erk wave generation and tissue size, in wild-type and when Erk waves are manipulated experimentally. We will identify the molecular nature of the Erk wave source using spatial transcriptomics and the potential feedback mechanism using live imaging and perturbations of signalling pathways.• Aim 2. In scale regeneration, at the transition from cell proliferation to hypertrophy, Erk dynamics switches from a high activity state to an excitable state with baseline low activity. We will investigate how Erk dynamics is regulated in time and space to control cell proliferation. First, we will use imaging to characterize how Erk dynamics is modulated and how it controls the transition from cell proliferation to hypertrophy. Second, we will test the hypothesis that mechanical cues regulate Erk dynamics, by inferring and perturbing mechanical forces and using imaging to relate them to Erk activity. Further directions. We will further investigate the role of Erk waves in scale regeneration and how osteoblasts coordinate with other tissues in scales. Thus, we will test the hypothesis that Erk activity waves are an efficient way to distribute growth-induced stresses across the scale and that they orchestrate bone tissue maturation. We will ask how different cell populations, e.g. bone-forming osteoblasts and bone-degrading osteoclasts, communicate to coordinate each other and regenerate a healthy scale. In the long term, we will extend this research program to the study of how signals coordinate the morphogenesis of complex appendages, such as fins, and organs.
Amount: CHF 1,763,000
Funding type: fellowship
Funder scheme: Eccellenza
Start date: 2022-05-01
End date: 2027-04-30
Investigator: De Simone, Alessandro
Institution: University of Geneva – GE
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 202776
OpenAlex ID: G4043350726