Apical constriction is a change in cell shape that drives critical morphogenetic events, including gastrulation and branching morphogenesis in diverse animals and neural tube formation in vertebrates. Although apical constriction was recognized more than a century ago, fundamental questions about mechanisms of apical constriction remain unanswered. Research in this laboratory focuses on understanding how cells accomplish this fundamental change in shape. Apical constriction is being studied to uncover insights into how animals are shaped, and to contribute to a foundation of basic science leading to improved diagnosis and prevention of neural tube defects. This proposal will support a series of projects to answer how the molecules that contribute to apical constriction generate and transmit the forces that change cell shapes, what triggers changes in cell shape, how developmental patterning mechanisms deploy cell biological players with the necessary spatial and temporal precision, and to identify and understand novel mechanisms that make important contributions to apical constriction. The laboratory has developed several key technical innovations to address critical barriers to progress in this field, and the proposed projects build on the lab's strength in dissecting cell biological mechanisms of development more generally. Study of apical constriction intersects with some of the major themes in cell and developmental biology including cell polarization, control of motor activity, and dynamic control of forces, in a complex in vivo context. The proposed projects seek to combine in a single model system the tools that are valuable to different model systems, plus the new tools that the lab has developed, to produce unique and sustained contributions to unraveling mechanisms that are relevant to critical morphogenetic events.
Neural tube defects (spina bifida and anencephaly, for example) constitute the second-most common class of birth defects, resulting in significant suffering and monetary costs: ~$1 billion total in hospitalization costs for all US patients each year. This proposal seeks to understand mechanisms of apical constriction, a change in cell shape that contributes to successful neural tube closure, using the roundworm C. elegans as a simple model for efficient investigation of cellular and molecular mechanisms. The long-term goal of the work is to understand fundamental mechanisms that can lay a foundation for future diagnosis and prevention of neural tube defects.
