Abstract
From the timing of amoeba development to the maintenance of stem cell pluripotency, many biological signaling pathways exhibit the ability to differentiate between pulsatile and sustained signals in the regulation of downstream gene expression. While the networks underlying this signal decoding are diverse, many are built around a common motif, the incoherent feedforward loop (IFFL), where an input simultaneously activates an output and an inhibitor of the output. With appropriate parameters, this motif can exhibit temporal adaptation, where the system is desensitized to a sustained input. This property serves as the foundation for distinguishing input signals with varying temporal profiles. Here, we use quantitative modeling to examine another property of IFFLs—the ability to process oscillatory signals. Our results indicate that the system’s ability to translate pulsatile dynamics is limited by two constraints. The kinetics of the IFFL components dictate the input range for which the network is able to decode pulsatile dynamics. In addition, a match between the network parameters and input signal characteristics is required for optimal “counting”. We elucidate one potential mechanism by which information processing occurs in natural networks, and our work has implications in the design of synthetic gene circuits for this purpose.
Highlights
IntroductionFrom Ca+2 signaling to coordination of cell fates, oscillatory signals are essential to regulation of cellular processes [1,2,3,4]
While the fundamental design principles underlying the generation of these oscillations are extensively studied, the mechanisms for decoding these signals are underappreciated
We demonstrate the capability of an Incoherent Feedforward Loop motif for the differentiation between sustained and oscillatory input signals
Summary
From Ca+2 signaling to coordination of cell fates, oscillatory signals are essential to regulation of cellular processes [1,2,3,4]. A systems-level approach to oscillation characterization examines the topologies in natural systems that give rise to pulse generation [9]. This demonstrates the necessity of ‘nonlinear’ kinetic rate laws for the destabilization of the steady state in the generation of oscillations [9]. While this constraint allows the generation of pulses with a diverse set of network motifs, negative feedback (especially negative feedback with a time delay) is found in all these cases. Even in the absence of any apparent regulation, transient oscillations in gene expression can emerge from cell-size control [11]
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