SUMMARY The diverse migratory modes displayed by different cell types are generally believed to be idiosyncratic. Here we show that the migratory behavior of Dictyostelium was switched from amoeboid to keratocyte-like and oscillatory modes by synthetically decreasing PIP2 levels or increasing Ras/Rap-related activities. The perturbations at these key nodes of an excitable signal transduction network initiated a causal chain of events: The threshold for network activation was lowered, the speed and range of propagating waves of signal transduction activity increased, actin driven cellular protrusions expanded and, consequently, the cell migratory mode transitions ensued. Conversely, innately keratocyte-like and oscillatory cells were promptly converted to amoeboid by inhibition of Ras effectors with restoration of directed migration. We use computational analysis to explain how thresholds control cell migration and discuss the architecture of the signal transduction network that gives rise to excitability.

Cellular protrusions are typically considered as distinct structures associated with specific regulators. However, we found that these regulators coordinately localize as propagating cortical waves, suggesting a common underlying mechanism. These molecular events fell into two excitable networks, the signal transduction network STEN and the cytoskeletal network CEN with different wave substructures. Computational studies using a coupled‐network model reproduced these features and showed that the morphology and kinetics of the waves depended on strengths of feedback loops. Chemically induced dimerization at multiple nodes produced distinct, coordinated alterations in patterns of other network components. Taken together, these studies indicate: STEN positive feedback is mediated by mutual inhibition between Ras/Rap and PIP 2, while negative feedback depends on delayed PKB activation; PKB s link STEN to CEN ; CEN includes positive feedback between Rac and F‐actin, and exerts fast positive and slow negative feedbacks to STEN . The alterations produced protrusions resembling filopodia, ruffles, pseudopodia, or lamellipodia, suggesting that these structures arise from a common regulatory mechanism and that the overall state of the STEN ‐ CEN system determines cellular morphology.

While directed migration may have evolved to escape nutrient depletion, it has been adopted for an extensive range of physiological events during development and in the adult. The subversion of these movements results in disease. Though the mechanisms of propulsion and sensing are extremely diverse, most cells move by extending actin-filled protrusions called macropinosomes, pseudopodia, or lamellipodia or by extension of blebs. In addition to motility, directed migration involves polarity and directional sensing. The hundreds of gene products involved in these processes are organized into networks of parallel and interconnected pathways. Many of these components are activated or inhibited coordinately with stimulation and on each spontaneously extended protrusion. Moreover, these networks display hallmarks of excitability, including “all-or-nothing” responsiveness and wave propagation. Cellular protrusions result from signal transduction waves which propagate outwardly from an origin and drive cytoskeletal activity. The range of the propagating waves and hence the size of the protrusions can be altered by lowering or raising the threshold for network activation, with larger and wider protrusions favoring gliding or oscillatory behavior over amoeboid migration. Here, we evaluate the variety of models of excitable networks controlling directed migration and outline critical tests. We also discuss the utility of this emerging view in producing cell migration and in integrating the various extrinsic cues that direct migration.

No abstract

Neural oscillations are evident across cortex but their spatial structure is not well- explored. Are oscillations stationary or do they form “traveling waves”, i.e., spatially organized patterns whose peaks and troughs move sequentially across cortex? Here, we show that oscillations in the prefrontal cortex (PFC) organized as traveling waves in the theta (4-8Hz), alpha (8-12Hz) and beta (12-30Hz) bands. Some traveling waves were planar but most rotated. The waves were modulated during performance of a working memory task. During baseline conditions, waves flowed bidirectionally along a specific axis of orientation. Waves in different frequency bands could travel in different directions. During task performance, there was an increase in waves in one direction over the other, especially in the beta band.