BBSRC-NSF/BIO: Synthetic Control of Pattern Formation and Morphogenesis in a Purposefully Rewired Vertebrate Cell

The goal of this project is to synthetically (artificially) control the behavior of the cell "cortex"—the outermost layer of the cell. It is the cortex that normally powers many fundamental biological processes, both within single cells, and in tissues and organs. Completion of the project will result in four important research outcomes: first, it will test current ideas about how living systems execute such processes as cell division, cell movement, and cell shape change.

Second, it will provide new tools and technologies that permit manipulation of cell behavior in living organisms. Third, it will provide the means to promote new, and potentially beneficial cell behaviors. Fourth, it will result in the development of new computational approaches for the analysis and understanding of complex cell behaviors.

Successful completion of the project will also lead to several important educational and training outcomes. This project, which is a collaboration between researchers at the University of Wisconsin-Madison (US) and the University of Edinburgh (UK), will support the training of two postdoctoral researchers and one graduate student in cell, molecular and computational biology, further preparing them for careers in science.

Moreover, an additional four-six undergraduate students will be trained in cell and molecular biology, preparing them for careers in science or medicine. Finally, four under-represented and financially underresourced high school students will be trained in cell and molecular biology for two consecutive summers and provided with additional training on how to succeed in college.

The training is anticipated to provide these students with the analytical and quantitative skills needed to excel in science, technology, engineering, and medicine related majors and, presumably, eventual careers in these areas.

The cell cortex is responsible for responding to a variety of internal and external signals with the appropriate mechanical behavior. Such behaviors include cell division, cell locomotion and short or long-term cell shape changes. This team and others recently discovered a dynamical process—cortical excitability—that a variety of cell types harness to drive distinct mechanical behaviors.

Cortical excitability is outwardly manifest as propagating cortical waves of actin assembly and complementary waves of the various macromolecules that control actin assembly. Cortical excitability is itself controlled by coupled fast positive feedback and delayed negative feedback. We will develop the means to synthetically induce cortical excitability in cells that do not normally display it, namely, frog oocytes, and employ high-resolution live cell imaging to capture the detailed features of excitability.

The induction will be based on synthetic protein constructs engineered to produce either fast positive feedback or delayed negative feedback. These constructs will be capable of generating different cortical excitability regimes either globally (ie throughout the entire cortex) or locally (ie in distinct regions of or patterns in the cortex). By combining different synthetic constructs, we will drive simple cell shape changes (ie furrowing) or complex cell shape changes (ie gastrulation), allowing us to test basic ideas about cell shape control.

In addition, by iteratively combining experiments with computational modeling of the results, it will be possible to develop both a quantitative, mechanistic understanding of processes such as cell division and morphogenesis. This research will be of interest to those working in a broad variety of scientific disciplines, ranging from cell and developmental biology to computational modeling, to physics.

Moreover, because the data generated will be extraordinarily rich in information, we anticipate that it will serve as a resource for many other researchers interested in dynamical behavior.

This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.