RESEARCH IN THE PARE LAB
We are using the fruit fly Drosophila melanogaster to uncover the molecular mechanisms that cells use to communicate spatial information with their neighbors during embryonic development. The early Drosophila embryo is an unparalleled model for studying cell behaviors during development, offering a wealth of genetic and imaging tools. Although a fruit fly is much simpler than a human, it is built using the same types of genes, proteins, and cells as we are. In fact, many of the biological principles discovered in the fly have proven to be universal throughout the animal kingdom––see the four Nobel prizes awarded to Drosophila studies in just the last 25 years.
(And it doesn't hurt that the embryos are quite beautiful.)
TOLL RECEPTOR SIGNALING AND CELL POLARITY
Toll-like receptors are well known for their functions in innate immunity, inflammation, and cancer progression. Paré and colleagues showed that Toll-related receptors also play an unexpected role in the early Drosophila embryo, where they are expressed in striped patterns. Striped expression of these cell surface receptors allows cells to infer their spatial orientation relative to the head-to-tail axis, causing cell intercalation and tissue elongation to proceed in a directional, rather than random, manner.
However, it is currently unknown how these receptors transmit and receive spatial cues at the molecular level. Toll receptors appear to be widely expressed in epithelial tissues throughout animal development. Therefore, elucidating the molecular mechanisms of Toll receptor activation could reveal a conserved role for these proteins in regulating cell polarity and epithelial tissue morphology in many biological contexts. These studies may also uncover unexpected links between immune signaling and cell shape change. We are using imaging, genetic, and molecular tools to address how Toll receptors signal to cytoskeletal and junctional complexes to effect changes in cell shape and behavior during development.
MOLECULAR LOGIC OF THE
LRR RECEPTOR CODE
There have been countless elegant genetic studies on transcriptional networks in early the Drosophila embryo that have been instrumental to our understanding of gene regulation during animal development. Broad overlapping domains of cross-regulatory transcription factors are iteratively refined over time to yield an amazingly precise, repeating array of transcriptional regulators along the anterior-posterior axis. Considering the fast pace of Drosophila development and the sheer density of transcriptional logic present in the early embryo, this system offers a unique opportunity to probe the extremes of cell signaling.
So what is the cell biological output of all this information? Perhaps the earliest output of this genetic system is the patterned expression of leucine-rich repeat (LRR) proteins at the cell surface. Three members of the Toll receptor family as well as Tartan are expressed in stereotypic partially overlapping stripes that create a repeating 8-cell-wide unit of spatial information. This “LRR code” bestows a unique molecular identity to each column of cells along the head-to-tail axis and serves as the symmetry breaking system that organizes cell polarity across the entire tissue. However, it is unknown why the code is laid out in the particular way that it is, and it is similarly unclear how these receptors interact with one another to control cell behavior. We are using a variety of imaging, genomic engineering, and computational techniques to address fundamental questions concerning how spatial information is encoded, transmitted, and actuated during development.
