REGCORD · Mechanisms of tissue size regulation in spinal cord development

How the organs of a developing organism achieve their correct size and shape is a fundamental unresolved question in biology. Mammalian embryos possess a remarkable ability to regulate (restore) the correct size of their tissues and organs upon perturbations during early development, yet how this is achieved is unknown. Addressing this question has so far been challenging because it requires a multiscale approach that integrates precise measurements with theoretical frameworks. We are now in an excellent position to unravel the mechanisms by which the mouse spinal cord regulates its size and shape during development by building on our experience with quantitative studies in this system. We previously obtained quantitative spatiotemporal data of growth, pattern and morphogen signalling dynamics in the spinal cord. We showed that there is a critical period during which morphogen signaling is interpreted to specify cell fates, uncovered a mechanism that allows precise pattern formation, and identified a link between the growth rate and tissue anisotropy. Our expertise now enables us to address the following new questions: 1) how is size regulation in the spinal cord achieved at the tissue and cellular level; 2) what is the molecular mechanism of size regulation, in particular the role of morphogen signaling; 3) how is the regulation of spinal cord size linked to the regulation of its shape. To address these questions, we will combine precisely controlled ex vivo assays in organoids and whole embryo culture, and in vivo advanced mouse genetics and mosaic analysis. We will obtain highly resolved dynamic data and interpret it in the context of rigorous theoretical frameworks. The project will advance our understanding of the fundamental mechanisms of tissue size control and the constraints they impose in regeneration and disease. Our results will have implications for in vitro tissue engineering and research on multi-organ coordination and robustness during development.