A zebrafish heart transforms from a simple tube into a complex, sponge-like meshwork as the embryo grows—and no one knows exactly how this happens. This project aims to uncover the physical and biological rules that guide that process. The problem is that while we know organs must develop precise shapes to work properly, the mechanisms that drive these shape changes remain poorly understood. The researchers will combine live imaging, biophysics, and computer modelling to watch the zebrafish heart build its internal mesh of muscle fibres, called trabeculae, in real time. They will test how the heart’s geometry directs cell behaviour, how fluid flow and the extracellular matrix contribute, and how the meshwork’s architecture is constrained even when development is perturbed. This is fundamental science—it will not produce a new drug or device tomorrow. But understanding how a heart reliably builds its own intricate structure could, in the longer term, inform tissue engineering efforts to grow replacement heart tissue, and help explain why certain congenital heart malformations arise when these processes go wrong.
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Building functional organs is critical for organismal growth and life, and thus organogenesis is a remarkably robust process. Yet, our understanding of how a developing organ acquires its characteristic form suited for its functionality remains rudimentary. To address this long-standing question, we will use a highly tractable model system, the developing zebrafish heart. As the embryo grows, the primitive myocardial wall of the zebrafish heart transforms from a monolayer epithelium into a complex 3D meshwork, which is critical for heart function. Yet, the mechanisms driving these crucial intricate topological transitions remain elusive. Thus, integrating quantitative imaging, biophysics, transcriptomics and theoretical modelling, we will uncover how form and function of a vital organ, the heart, emerge reproducibly during development. We will elucidate – 1) how geometry confines cellular processes locally to pattern the myocardial tissue, and if this entails localized extracellular matrix remodelling and altered fluid mechanics, 2) how ventricular meshwork architecture, called trabeculae, are shaped, constrained, and canalized during development and perturbations, and how this affects heart function, and 3) mechanisms underlying atrial meshwork morphogenesis. These findings will reveal fundamental design principles underlying robust organogenesis, yield a rational framework for tissue engineering efforts and improve our understanding of cardiac malformations.
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