On the principles of cell decision-making: intracellular coupling improves cell responses fidelity of noisy signals

Abstract

Reliability of cell fate decision-making is crucial to biological development. Until today it has not been clear what are biology's design principles that allow for reliable cell decision making under the influence of noise. Here, we attempt to answer this question by drawing an analogy between cell decision-making and information theory. We show that coupling of intracellular signalling pathway networks makes cell phenotypic responses reliable for noisy signals. As a proof of concept, we show how cis-interaction of the Notch-Delta pathway allows for increased performance under the influence of noise. Interestingly, in this case, the coupling principle leads to an efficient energy management. Finally, our postulated principle offers a compelling argument why cellular encoding is organized in a non-linear and non-hierarchical manner.Intoduction.− Cell decisions are responses of cell's internal mechanisms to external signals [1]. Such mechanisms are typically termed as signal transduction pathways. Signal transduction occurs when an extracellular signalling molecule bounds to a certain receptor creating a complex. In turn, this complex of molecules triggers a biochemical chain of events inside the cell, leading to a phenotypic response [2]. These responses are required to be of high fidelity and reliability since they are related to vital organism processes, such as cellular metabolism, shape, differentiation, or mitotic activity [3].Signal transduction pathways can be considered as input-output communication channels. Each pathway involves a number of key interacting proteins. The chain of biochemical events that involves the reception, endocytosis, activation/inactivation, nucleus internalisation, degradation or exocytosis of such a protein defines a single processing channel, in terms of encoding and decoding. The network of interactions of these coupled proteinchannels defines the signal transduction channel.Signal transduction pathways are subject to noisy perturbations. Typically, intracellular or intrinsic noise corresponds to thermal/stochastic fluctuations of the involved protein interactions. Alternatively, it may also account for any unknown and unobserved protein. Extrinsic noise lumps phenomena that contribute to stochasticity in cell-cell or cell-microenvironment communication.In this paper, we seek answers on biology's design principles that allow for reliable cell decision-making under the influence of noise. By means of a minimalistic communication model, we show that channel coupling can enhance the information capacity. In turn, we focus on dynamic cell fate determination processes, such as the Notch-Delta pathway, by establishing an analogy with communication theoretical concepts. We show that pathway coupling improves the reliability of responses in noisy * haralampos.hatzikirou@helmholtz-hzi.de environments which, thus, can be considered as a mechanism for robust cell-decision making.From information theory to cell decision-making.− Cells can be viewed as decision-makers that constantly proce...