Tissue Mechanics in Neural Tube Morphogenesis

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Tissue morphogenesis depends on the intrinsic and extrinsic forces acting on tissue soft matter properties. These physical quantities are the final effectors and the converging point of the genetic and environmental interactions that control morphogenesis. In the developing neural tube, a multitude of genetic and cellular processes contribute to its folding and closure, yet how they regulate tissue mechanics remain unclear. The failure of closure leads to neural tube defects (NTDs), a class of common developmental abnormalities and a worldwide health burden. To resolve NTD etiology, it is essential to define the tissue forces that drive neural tube folding and uncover their genetic and cellular origins and regulation. The avian neural tube shares key morphogenetic characteristics with humans while providing easy access to imaging and mechanical tools. Recently, I and colleagues developed a novel force probe for direct tissue stress measurement and loading in live avian embryos. Importantly, we identified a compression force from the presomitic mesoderm and a change of global tissue tension, both required for neural tube folding suggesting previously unrecognized NTD causes. The dynamics of these forces, tissue rheological properties, and their interplay with cellular and genetic processes are unknown. Here, combining quantitative tissue mechanics and imaging, I propose to 1) systematically map tissue mechanics and cell and extracellular matrix organization of the avian neural tube and neighbouring tissues; 2) elucidate the role of planar cell polarity and folate pathways in inter-tissue mechanics during neural folding; 3) define the cellular mechanisms controlling the formation and pressure of the neural tube lumen. Our insights will transform our understanding of NTDs and more generally the mechanics of epithelial morphogenesis. Our quantitative platform will have broad applications in other models of morphogenesis, including human organoids.