Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis

Collective cell responses to exogenous cues depend on cell-cell interactions. In principle, these can result in enhanced sensitivity to weak and noisy stimuli. However, this has not yet been shown experimentally, and, little is known about how multicellular signal processing modulates single cell sensitivity to extracellular signaling inputs, including those guiding complex changes in the tissue form and function. Here we explored if cell-cell communication can enhance the ability of cell ensembles to sense and respond to weak gradients of chemotactic cues. Using a combination of experiments with mammary epithelial cells and mathematical modeling, we find that multicellular sensing enables detection of and response to shallow Epidermal Growth Factor (EGF) gradients that are undetectable by single cells. However, the advantage of this type of gradient sensing is limited by the noisiness of the signaling relay, necessary to integrate spatially distributed ligand concentration information. We calculate the fundamental sensory limits imposed by this communication noise and combine them with the experimental data to estimate the effective size of multicellular sensory groups involved in gradient sensing. Functional experiments strongly implicated intercellular communication through gap junctions and calcium release from intracellular stores as mediators of collective gradient sensing. The resulting integrative analysis provides a framework for understanding the advantages and limitations of sensory information processing by relays of chemically coupled cells.Comment: paper + supporting information, total 35 pages, 15 figure

Protein trafficking in the mitochondrial intermembrane space: mechanisms and links to human disease

Mitochondria fulfill a diverse range of functions in cells including oxygen metabolism, homeostasis of inorganic ions and execution of apoptosis. Biogenesis of mitochondria relies on protein import pathways that are ensured by dedicated multiprotein translocase complexes localized in all sub-compartments of these organelles. The key components and pathways involved in protein targeting and assembly have been characterized in great detail over the last three decades. This includes the oxidative folding machinery in the intermembrane space, which contributes to the redox-dependent control of proteostasis. Here, we focus on several components of this system and discuss recent evidence suggesting links to human proteopathy

Molecular communication in fluid media: The additive inverse Gaussian noise channel

We consider molecular communication, with information conveyed in the time of release of molecules. The main contribution of this paper is the development of a theoretical foundation for such a communication system. Specifically, we develop the additive inverse Gaussian (IG) noise channel model: a channel in which the information is corrupted by noise with an inverse Gaussian distribution. We show that such a channel model is appropriate for molecular communication in fluid media - when propagation between transmitter and receiver is governed by Brownian motion and when there is positive drift from transmitter to receiver. Taking advantage of the available literature on the IG distribution, upper and lower bounds on channel capacity are developed, and a maximum likelihood receiver is derived. Theory and simulation results are presented which show that such a channel does not have a single quality measure analogous to signal-to-noise ratio in the AWGN channel. It is also shown that the use of multiple molecules leads to reduced error rate in a manner akin to diversity order in wireless communications. Finally, we discuss some open problems in molecular communications that arise from the IG system model.Comment: 28 pages, 8 figures. Submitted to IEEE Transactions on Information Theory. Corrects minor typos in the first versio

Capacity of a Simple Intercellular Signal Transduction Channel

We model the ligand-receptor molecular communication channel with a discrete-time Markov model, and show how to obtain the capacity of this channel. We show that the capacity-achieving input distribution is iid; further, unusually for a channel with memory, we show that feedback does not increase the capacity of this channel.Comment: 5 pages, 1 figure. To appear in the 2013 IEEE International Symposium on Information Theor