Understanding the temporal codes of intra-cellular signals

Abstract

The health of organisms and cells depends on appropriate responses to diverse internal and external cues, stimuli, or challenges, such as changes in hormone or cytokine levels, or exposure to a pathogen. Cellular responses must be tailored to the identity and intensity of the stimulus and therefore intra-cellular signals must carry information about both. However, signaling mediators often form intricate networks that react to multiple stimuli yet manage to produce stimulus-specific responses. The multi-functionality ('functional pleiotropism') of signaling nodes suggests that biological networks have evolved ways of passing physiologically relevant stimulus information through shared channels. Increasing evidence supports the notion that this is achieved in part through temporal regulation of signaling mediators' activities. The present challenge is to identify the features of temporal activity profile that represent information about a given stimulus and understand how cells read the temporal codes to control their responses.

Figure 1. Features of the Stimulus are encoded in features of the signal, determine the expression of genes

(A) Features of the stimulus, such as its type (identity), amplitude, duration, or frequency, are encoded by receptor-associated signaling networks into different features of the intra-cellular signal's temporal profile. Gene regulatory networks decode the information contained in the features of the signal's temporal profile and thus determine whether a specific gene is activated and by how much. (B) An example of a timecourse of an amplitude-modulated intra-cellular signal and potential coding features: Transient and steady state amplitudes, transient duration, duration over a threshold, number and time between peaks, etc.

Figure 2. Temporal profiles can carry specific signal information for multiple pathways

(A) Decoders A, B, and C, represented here by different gene regulatory networks, are sensitive to particular dynamical features of the signaling mediator's activity. Decoder A responds to early strong signals, decoder B is requires longer lasting signals regardless of the amplitude, whereas decoder C detects late strong signals. In this example, encoders associated with different receptors produce stimulus-specific temporal patterns that control the nature of the response. (B) The temporal code allows shared signaling mediators to respond properly to simultaneous stimuli.

Figure 3. Decoding mechanisms define the signaling code in complex signals

Stimulus X, Y, and Z are encoded into complex signals. The presence or absence of specific dynamical features determines the what feature of the temporal signaling profile the decoders respond to. In this example, response B is common to stimuli A, Y., Z, but response A and C are more stimulus-sepcific.