PROJECT SUMMARY / ABSTRACT Collective migration of epithelial cells plays central roles in morphogenesis, intestinal turnover, wound repair, and metastasis. Epithelial cells use the same migration machinery as individual cells. For an epithelial sheet to migrate, however, this machinery must become globally aligned across the tissue plane. Determining how this tissue-level polarization is achieved is a central goal of the collective migration field. We study a rotational form of epithelial migration that occurs when the tissue is confined to a circular or spherical geometry. Rotational migrations differ from other epithelial migrations in two ways. First, external cues like empty space or chemo- tactic signals are not available to guide tissue polarization. Instead, the cells must rely solely on local cell-cell interactions to achieve this state. How cells self-organize for rotational migration is unknown. Second, there is no net tissue movement, which raises the question of why these migrations occur. Rotation promotes the assembly of the basement membrane extracellular matrix that lines the tissue’s basal surface; it can even create highly structured basement membranes that direct organ morphogenesis. However, how rotation impacts basement membrane assembly is poorly understood. Notably, recent work has shown that epithelial rotation may contribute to human organ development, as the spherical alveoli of mammary organoids rotate as they form despite being connected to a central ductwork. My NIGMS-funded research has two goals: (1) to define the local cell-cell interactions that allow epithelial cells self-organize for rotational migration, and (2) to determine how rotation structures the basement membrane. To this end, we are studying a rotational migration that occurs in the follicular epithelium of the Drosophila. In recent years, we used this model to provide the first insight into the local cell-cell interactions that polarize an epithelium for rotational migration by identifying a novel planar signaling system that mediates this process. We also showed that rotation works with new protein secretion to create fibrils in the basement membrane that control tissue shape. Through the MIRA program, we will dig deeper into both mechanisms. We will determine how the planar signaling system allows the follicle cells to break symmetry and initiate migration and how the signaling works at molecular level - both in terms of how the proteins interact with one another and with the migration machinery. We will also explore two mechanisms by which mechanical forces imparted by rotational migration are likely to influence basement membrane assembly. This work will reveal new guiding principles for how tissue-level order can emerge from local cell-cell interactions. Moreover, because basement membranes are central to most organs and defects in their assembly underly muscular dystrophy, nephropathy, skin blistering, and stroke, anything we learn about this poorly understood process will have broad impact.

PROJECT NARRATIVE The collective migration of epithelial cells plays key roles in tissue morphogenesis, intestinal turnover, wound repair, and metastasis. For an epithelium to migrate, the cell migration machinery that powers each cell’s movement must become aligned across the tissue. The goal of this research is to use the genetic tractability of fruit flies to determine :(1) how epithelial cells become organized for collective motility, and (2) how this motility can be harnessed to structure extracellular matrix over which the cells migrate.