Physics of Living Matter: From Molecule to Embryo.

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ABSTRACT Shape is critical for proper organ function. For example, neural tube morphogenesis lays the foundations of brain and spine. Neural tube defects that fail to close the tube have devastating consequences for the body. Despite success with folic acid treatment, we are still missing effective treatment strategies. From genetic model systems, we have learned much about the principles of how morphogens setup body axes, and trigger a cascade of regulatory factors that precisely pattern the organism, endowing each cell with a unique fate. However, morphogenesis, the question of how genes instruct form, also involves aspects of mechanics. Tissue folding requires the coordinated action of forces that dramatically change the form of the organ. From single cell studies in vitro, we have learned how cells utilize fundamentally dynamic processes that involve their cytoskeleton to generate forces. However, how forces are coordinated across tissues to reliably generate form remains elusive. Progress requires extending molecular analysis to investigation of cellular dynamics at the organ level, to study the interplay of forces and cell behaviors. Organ shape is instructed by patterns of forces generated from dynamic processes observed in cell behaviors. While we are beginning to monitor the dynamics of cell behaviors, measuring these force patterns in animal model systems remains very challenging. Moreover, animal development differs in key aspects from humans. This is particularly true for neural development, and its derived structure the brain. To overcome these hurdles, we have developed a new stem cell model for neural tube closure in a human genetic context. Our approach is inspired by embryogenesis, and first organizes cells into a closed sheet surrounding a lumen. In this way we guide stem cells in terms of fate and form, but leave enough room for a dynamic, and self-organized morphogenetic program. The results are multiple complex and interacting human tissues, which exhibit striking similarity to the in vivo analogue in terms of genetic pattern, shape, and reproducibility. This proposal seeks to enter new territory in the study of mechanical aspects of neural tube closure in a human genetic context. To this end, we exploit the unique capabilities of our stem cell model system to undergo complex morphogenetic processes in the precisely controlled and for quantitative measurements highly suitable environment of a petri dish. Specifically, this environment allows us to directly measure absolute levels of forces in a faithful stem cell model of human neural tube closure. In addition, this setup allows us to investigate how cells handle geometric constraints at the tissue level – a process that has been linked with one of the most devastating forms of neural tube closure defects. Our stem cell-based approach will open up new paths towards deciphering how human genetics works in health and disease.