Mechanics of mammalian morphogenesis

Morphogenesis requires careful regulation across multiple dimensions to ensure proper positioning and identity of differentiating progenitor cells. Ultimately, differentiating cells must coordinate multiple physical parameters - their environment, position, proliferation and shape - and use these cues to inform their final state and function. One such cellular shape change broadly utilized to produce complex tissue architectures is apical constriction: the shrinkage of the apical domain of cells to become wedge-shaped. Apical constriction cumulatively drives tissue shape changes during various key developmental processes, including gastrulation and branching morphogenesis. The majority of what we have learned about the physical and regulatory features of apical constriction come from non-mammalian model organisms, primarily invertebrates. Whether mammalian tissues use conserved or distinct apical constriction mechanisms and machinery has not been elucidated, nor is it clear how this conserved biophysical phenomenon can be so flexibly utilized across multiple disparate developmental transitions. Although apical constriction machinery generally converges on the same conserved proteins, their spatiotemporal dynamics vary widely across contexts and species. We aim to identify the proteins that direct mammalian apical constriction, define their spatiotemporal dynamics, and connect the induction of this pathway to core genetic drivers. We will uncover the general principles that ensure robustness and mechanical integrity by examining diverse developmental contexts where apical constriction is a fundamental morphogenic feature. Over the next five years, we will address how cell shape changes initiate and control morphogenesis by answering the following questions: 1) What force-generating mechanisms drive mammalian apical constriction? 2) What molecular mechanisms regulate cortical reorganization during apical constriction? 3) How do developmental cell fate transitions license physical aspects of cell shape? To ensure our findings can be broadly generalized, we will investigate multiple systems where apical constriction is essential, including primary intestinal cell culture and the early mouse embryo. Specifically, we model apical constriction in intestinal crypt formation, primitive streak formation and neural tube formation. These systems will allow us to investigate the dynamics of mammalian apical constriction, localization of key machinery components, protein-protein interactions, and the transcriptional networks that control the timing of their induction. These studies will produce deep insight into the mechanisms driving one of the most widely used morphogenetic cell shape changes, identify novel factors that direct the process, and connect the regulation of cell state to essential physical features. Together, this knowledge will establish a fundamental understanding of how mammalian tissues coordinate morphogenesis. The proposed project aligns with my research group's long-term vision to define cellular mechanisms controlling tissue patterns to understand how architecture regulates cell fates and behaviors.