Principles of Addressing Specificity in Promiscuous Ligand-Receptor Systems

Author: Su, Christina Janet

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Elowitz, Michael B.

Committee Members: Chan, David C.; Elowitz, Michael B.; Goentoro, Lea A.; Thomson, Matthew

Option: Systems Biology; Computer Science

DOI: 10.7907/z7dv-m192

Abstract

In multicellular organisms, a relatively small number of highly conserved signaling pathways are used to enable intercellular communication. While the underlying molecular components and interactions are increasingly well understood, a fundamental mystery is how the diverse cell types of the body can be so precisely coordinated by so few pathways. It has long been known that different cell types exhibit varied responses to molecular signals, and it is unclear how this cell type specificity arises. In this work, we take a different perspective on this question and explore how cell type specificity can be generated at the level of intracellular signal. We refer to this ability to selectively activate different cell types as "addressing." By eliminating the complexity of considering downstream pathway effectors, we are able to more comprehensively understand how cell type specificity can arise in spite of—or because of—promiscuity in ligand-receptor interactions. We focus on the bone morphogenetic protein (BMP) pathway as an ideal example. This pathway is essential in development, is of therapeutic interest in an array of pathologies, and has proven amenable to theoretical and experimental analysis. We first describe a minimal model of the pathway and identify what types of response functions can be achieved. We show that each layer of computation, from the formation of signaling complexes to the activation of downstream second messenger, can provide nontrivial integrations of ligand inputs. We then extend this analysis to systems with multiple cell types that may vary in receptor expression profile. The diverse response functions of this pathway enable systems in which different cell types or sets of cell types may be addressed with high specificity. In particular, the BMP pathway can address multiple cell types with high capacity, flexibility, and robustness. Taken together, these results provide a framework for understanding how molecular promiscuity in signaling pathways can, in fact, enable cellular specificity in pathway responses.

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