Orion D. Weiner
Research Interests
How Cells Establish Polarity and Guide Movement
Many eukaryotic cells have the capacity to polarize and migrate in response to external gradients of chemoattractant. Directed motility is essential for single-celled organisms to hunt and mate, axons to find their way in the developing nervous system, and cells in the innate immune system to find and kill invading pathogens. We are only beginning to understand the circuitry of the internal 'compass' used by eukaryotic cells to regulate polarity during chemotaxis. Our research focuses on identifying key missing components of the cellular compass and determining how the overall signaling network is wired together to coordinate the many activities involved in directed cell polarity. Our model systems for these studies are neutrophils (one of nature's master migratory cells) and neutrophil lysates, which contain very high concentrations of many proteins that regulate polarity.
Figure 1. Human neutrophil
(from my finger) polarizing in response to gradient of
chemoattractant.
Part of our research focuses on identifying core circuits of cell
polarity. We discovered a positive feedback loop involving the
GTPase Rac, the lipid PIP3, and actin polymers that plays
a central role in generating neutrophil polarity.
Analogous feedback loops are now known to be essential for polarity
in cells ranging from yeast to Dictyostelium to neutrophils.
To uncover novel components of this circuit, we used a combination
of classical protein purification and reverse genetics to identify a
set of protein complexes (Hem-1 containing complexes) that are
essential for the feedback loops that control cell polarity in
neutrophils. We suspect this scaffold may orchestrate an entire
program of polarity effectors that act at the leading edge during
chemotaxis, and we are currently dissecting the inputs and outputs
of this essential polarity circuit.
We are developing techniques to deconstruct and reconstitute key polarity circuits in vitro and spatially manipulate and monitor signaling in vivo in our quest to understand how these amazing migratory cells work. This knowledge is essential if we are to ultimately control inflammation, cancer metastasis, and other processes that depend on properly guided cell movement.
Named Scientist Magazine, Top 10 innovations of 2009 and Science Signaling Magazine 2009: Signaling Breakthroughs of the Year