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.