Cells are complex objects. They communicate with one another, collect information, and perform computations. Within a multicellular body, cells individually follow simple rules that give rise to rich collective behaviors. To study such cellular dynamics, we use quantitative tools to analyze cells’ activities to discover the underlying rules they follow.
How nuclei proliferate and arrange themselves within a single giant cell
SUMMARY: In some cell types, many nuclei share a single large cytoplasm. As those nuclei divide and move within the cell, they need to end up in the right arrangement at the right time. Do individual nuclei “know” where to go? Or are there nearby signals they can follow? Or something else? This has puzzled cell biologists for more a century. My collaborators and I set out to study this phenomenon in insect embryos because they are especially well-suited for in-lab experiments. With a combination of time-lapse imaging, computational modeling, and physical manipulation of embryos, we learned that seemingly complex behaviors emerge from just a few extremely simple rules, based on local nucleus crowding.
Along the way I also designed and built a new experimental apparatus to physically manipulate tissue shape to test our core hypothesis:
For a walkthrough of the project and the story behind it, I recommend the write-up in the New York Times: “The Mysterious Dance of the Cricket Embryos.” The article does not go into the logic of the research; it is more focused on the experiences and thoughts of the researchers themselves (myself included). I was astonished to see how much meticulous work was done by the writer Siobhan Roberts as she crafted and checked the drafts.
The article also includes a glimpse of my little home lab and the actual notebook I used during the project. The photo shows sketches of competing models of cell movements that we tested along the way (photo by Mustafa Hussain).
How cells store and share directional information
SUMMARY: In order to function properly, cells often need to “know” things beyond the information encoded in their genome. One thing a cell needs to know is how it is oriented with respect to the arrangement of the other cells in its tissue; this is called cell polarity. In this project I used high-throughput measurements of many cells in the epidermis of the fruit fly to determine how different genes contribute to cell polarity.
Cells in a tissue need to coordinate their divisions and shape changes. For epithelial tissues—that is, sheets of cells—some of that coordination is accomplished by all the cells “knowing” their orientation within the plane of the epithelium. They also check with their neighbors and adjust accordingly, which increases polarity alignment across the tissue.
This directional information is called planar polarity. Two groups of genes—the Dachsous (Ds) and Frizzled (Fz) “systems”—play key roles in establishing and maintaining such planar polarity. We studied the activity of the Ds and Fz gene groups in the Drosophila ventral epidermis (i.e. belly skin). This tissue is useful for studying planar polarity because the cells do something unusual: they make visible structures that demonstrate their polarization.
The above left image is a zoomed-in view of the larva’s abdomen. There are little pigmented cuticle hooks called denticles that the larva uses to grip the ground at it crawls. Those denticles are secreted by the cells, and each one points in a direction that is set by the planar polarity of cell that secreted it.
This means that we can manipulate which genes are expressed in subsets of cells, and then measure the underlying planar polarity by examining the orientation of cuticle protrusions called denticles.
I developed an automated image analysis workflow to quantify the exact orientation angle of each denticle in the epidermis, thereby detecting subtle planar polarity defects in mutant larvae. We showed that the Ds and Fz systems contribute independently to polarity in spatially distinct domains, with the role of the Ds system changes as the tissue grows. Lastly, we found that Ds and its receptor, Fat, are enriched in distinct patterns in the epithelium during embryonic development.
In other words, we discovered that two groups of genes separately imbue cells with the same sort of cell polarity, but each group has a particular subset of cells where its effect is strongest.
How a group of cells coordinate its movements
SUMMARY: When a group of cells moves together, they often track an external cue or have “leaders and followers”. In some cases, however, a group of cells forms a continuous circular path with no external cues and no leaders. So how do they coordinate their movements so that they all go in the same direction? This project, led by Audrey Williams, addressed this question using a well-studied migratory tissue in the fruit fly.
This is a short time-lapse of the tissue we studied. The cells are adhered to one another. They move by forming protrusions and anchoring to an underlying protein matrix.
My main contribution to the project was to write a custom software tool to automatically segment the dynamic protrusions of the cells.