Cell Biology, Developmental Biology
Memorial Sloan Kettering Cancer Center
Dr. Zallen is also a member in the Developmental Biology Program at Sloan Kettering Institute in the Memorial Sloan Kettering Cancer Center. She was an HHMI early career scientist from 2009 to 2015.
How Collective Cell Movements Lead to Tissue Structure
As an embryo grows and transforms, its cells divide, shift, and take on new identities. Jennifer Zallen is studying the coordinated cell movements that shape the emerging animal form. She studies how large populations of young cells reorganize to become the elongated beginnings of a body, a transition that requires hundreds of cells to align their movements along a common axis. Working on the fruit fly, her research team discovered that cells at this early stage form pinwheel-shaped rosettes, in which groups of cells line up and then rapidly reorganize themselves to create distance between the fly's future head and tail. This process involves coordinated contractile structures that extend across multiple cells, contracting and pulling the cluster into a rosette. This rosette mechanism has now been shown to be a fundamental strategy for tissue elongation that is conserved from flies to mammals. In addition, Zallen's team has identified a molecular code that systematically orients cell movements throughout the embryo and orchestrates this dramatic shape change. This work, unraveling the molecular signals and biophysical forces that shape developing embryos, is an important foundation for understanding how errors in these processes lead to birth defects, kidney disease, and cancer.
Elongation is no small matter for animals. Whether human or fruit fly, one of the first steps in the development of an embryo is to put some space between top and bottom. This process happens at high speed in the fruit fly, Drosophila melanogaster. Three hours after fertilization, a tiny embryo consisting of about 6,000 cells starts to stretch out. It goes on to double in length and narrow by half in less than an hour.
Until recently, it was not clear how the embryonic fly carried out this bioengineering marvel. Jennifer Zallen of New York's Memorial Sloan-Kettering Cancer Center has combined high-resolution, time-lapse microphotography with quantitative computational analysis to throw light on the process.
The fly embryo elongates not by producing more cells but by reorganizing existing cells. Zallen discovered that the cells don't travel as individuals, with each one moving inexorably toward a specific target site. Instead, they coordinate movements with their neighbors, forming pinwheel-shaped "rosette" clusters where groups of cells line up from front to back and then rapidly reorganize to expand from head to tail, pushing the embryo's head away from the rear. Using custom-developed computer programs to track hundreds of cells over time, Zallen's lab found that more than 85 percent of the cells form rosettes and more than half of them join one rosette after another. These organized, tag-team behaviors provide an efficient way to rapidly transform the embryo from a ball into a long, narrow tube.
Zallen owes some of the quantitative precision of her work, in a roundabout way, to the fact that she ignored her father's advice. Her father, Richard Zallen, is a condensed-matter physicist at Virginia Tech in Blacksburg, where she grew up.
As a student, Zallen resisted her father's urgings to become a physicist, believing that biology offered more interesting problems to solve. Later on, Zallen asked her dad to look at her microscale photographs of elongating fly embryos. The cell pattern reminded him of foams, and he noticed that fruit fly cells show increasing complexity in terms of their topologies - or neighbor relationships - as they rearrange.
Obviously, embryos are different from foams, says Zallen, but the analytic methods physicists worked out to describe foams' physical characteristics have given her a new tool for tracking the behavior of living cells. She explained this concept in a paper published together with her father.
Zallen's lab contains geneticists, cell biologists, and computer scientists who are developing automated tools to probe what's going on in the embryo by systematically analyzing hundreds of cells at once. This additional data-crunching capacity will be critical in Zallen's next project: to run a massive genome-wide search for genes in Drosophila that drive elongation. The elongation process, she explains, ultimately comes down to genes - genes that allow cells to move, instruct them where to go, and tell them when to stop. Zallen will use a process called a forward genetic screen to randomly turn genes off one by one in hope of finding mutant fly embryos that fail to elongate and instead stay in the shape of a ball.
Genes required for elongation could be anywhere in the genome. Only the fly, in the form of a mutant animal, can reveal their location. It is a slow, expensive exploration with no guarantee of success. And yet, says Zallen, forward genetic screens have paid off time after time in the history of developmental biology. "You don't know what you're going to find so you're not limited by your assumptions. The genes that surprise us are often the ones that really advance the field," says Zallen.
Zallen's lab is also exploring how cells use mechanical forces to communicate with each other during elongation. The researchers use laser technology to blast tiny holes in the embryo to measure the forces generated by cells tugging on each other. They also use biophysical methods to apply controlled forces to a cell and watch how it responds. "Mechanical signals," says Zallen, "can allow cells to respond rapidly to changes happening in their neighbors, and these signals have the potential to travel even further than typical biochemical cues."
The elongation process is so fundamental that Zallen believes the principles of fly elongation will be relevant to other animals, including humans. If so, there is a good chance that human counterparts of fly elongation genes could be important for disease processes like tumor metastasis, where cells break free from existing tumors and reorganize in new locations. Elongation genes are also likely to play critical roles in human embryonic development, and their discovery may shed light on the causes of birth defects.