HIGHLIGHTS
A self-organizing circuit for cell movement.
Actin polymerization is important for cell shape and movement, but how cells regulate the dynamics of this process is not well-understood. Here we discovered a self-organizing circuit that enables a key actin regulator (the WAVE complex) to control cell movement. Reciprocal interactions of the WAVE complex and the actin cytoskeleton generate propagating waves of actin nucleation that could explain many of the properties of morphogenesis in motile cells, including the ability of cells to flow around barriers and the dynamics of protrusion at the leading edge.
Weiner OD#, Marganski WA, Wu LF, Altschuler SJ, Kirschner MW#.
PLoS Biology, 5(9): e221 (2007). (#corresponding author)
How cells prioritize a single protrusion.
During cell migration, protrusions exert long-range inhibition over one another to enable a winner-take-all. This communication was thought to depend on the diffusion of regulatory molecules across the cell, but we found that this inhibition is actually relayed by physical forces. In particular, actin polymerization-based protrusions increase tension in the plasma membrane, which in turn acts as a long-range inhibitor of actin assembly. Our work highlights the important reciprocal dialogue between biochemical signals and physical forces in integrating complex behaviors.
Houk A, Jilkine S, Mejean CO, Boltyanskiy R, Dufresne ER, Agenent S, Altschuler SJ, Wu LF, Weiner OD.
Cell, 148: 175-188 (2012).
The role of timing in signal specificity.
The Ras/MAPK cascade is a shared signaling module for a broad suite of upstream inputs. It controls a diverse array of physiological responses, including differentiation, proliferation, and arrest. How does the cell know which response to initiate following Ras/MAPK activation? By directly manipulating the Ras/MAPK cascade with light-based optogenetic tools, we showed that the temporal dynamics of this cascade is sufficient to instruct appropriate physiological responses. We also identified novel effectors that are triggered by specific Ras/MAPK dynamics. Our precision optogenetic tools enable complex cell behaviors to be dissected with in vivo biochemistry.
Toettcher JE, Weiner OD#, Lim WA#.
Cell, 155: 1422-1434 (2013). (#corresponding author)
Force-based integration of cell movement.
Cell movement is coordinated by reciprocal interactions between the actin cytoskeleton and mechanical forces. The plasma membrane is thought to directly inhibit actin assembly by serving as a physical barrier that opposes protrusion. Here we show that control of actin polymerization-based protrusions requires an additional (PLD2/mTORC2-based) mechanosensory feedback cascade that links membrane tension with actin nucleation. This cascade prevents expansion of the existing front and the formation of secondary fronts.
Diz-Muñoz A, Thurley K, Chintamen S, Altschuler SJ, Wu LF, Fletcher DA, Weiner OD.
PLoS Biology, 14: e1002474 (2016).
How T cells distinguish foreign from self.
To detect rare antigenic peptides in a sea of self-peptide, T cells are thought to convert small changes in ligand binding half-life to large changes in cell activation. Such a kinetic proofreading model has been difficult to test directly, as we have lacked tools to specifically manipulate ligand binding half-life. We developed an optogenetic approach to specifically tune the binding half-life of a light-responsive ligand to a T cell receptor without changing other binding parameters. Our results provide direct evidence of kinetic proofreading in ligand discrimination in T cells and reveal where in the signaling cascade this computation is executed.
Tischer D, Weiner OD.
eLife, 8: 42498 (2019).
More than one way to move.
Actin polymerization plays an important role in controlling the shape and dynamics of motile cells. Here we tested the importance of the primary actin regulators (WAVE and the Arp2/3 complex) in cell movement. These regulators proved to be essential for migration in standard conditions but were dispensable for movement under compressive environments—in this context, the cells move with hydrostatic blebs instead of actin-based protrusions. Our work highlights the flexibility of the cell migration machinery in different cellular environments.
Graziano BR, Town JP, Sitarska E, Nagy TL, Fošnarič M, Penič S, Iglič A, Kralj-Iglič V, Gov NS, Diz- Muñoz A, Weiner OD
PLoS Biology, 17: e3000457 (2019).
Genome organization and transcriptional regulation.
Enhancers are non-coding regulatory elements that control gene activity over vast genetic distances. To better understand how enhancers influence target gene expression, we developed tools to follow enhancer-promoter interactions and transcriptional activation in living mouse embryonic stem cells. Our work revealed that direct enhancer-promoter contacts do not drive contemporaneous gene activation, challenging the textbook model of enhancer function.
Alexander JM, Guan J, Huang B, Lomvardas S, Weiner OD.
eLife, 8: 41769 (2019).
A self-organizing template for cell shape.
How local interactions of actin regulators yield large-scale organization of cell shape and movement is not well understood. Here we investigate how the WAVE complex organizes sheet-like lamellipodia. Using super-resolution microscopy, we find that the WAVE complex forms actin-independent 230 nanometer-wide rings that localize to regions of saddle membrane curvature. This pattern of enrichment could explain several emergent cell behaviors, such as expanding and self-straightening lamellipodia and the ability of endothelial cells to recognize and seal transcellular holes. Our work reveals how feedback between cell shape and actin regulators yields self-organized cell morphogenesis.
Pipathsouk A, Brunetti RM, Town JP, Breuer A, Pellett P, Marchuk K, Tran NHT, Krummel MF, Stamou D, Weiner OD (2019).
bioRxiv
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