Requirements for efficient cell-type proportioning: regulatory timescales, stochasticity and lateral inhibition

TL;DR

This paper models the dynamics of cell-type proportioning in multicellular organisms, highlighting how dual-time feedback loops enhance robustness amid stochasticity and lateral inhibition.

Contribution

It introduces a modeling framework using inhibitory-coupled noisy bistable systems to analyze developmental regulation of cell proportions and proposes a dual-feedback strategy for improved regulation.

Findings

Stable two-cluster states in the model

Dual-time feedback loops improve proportion regulation

Mechanisms balance early flexibility and late commitment

Abstract

The proper functioning of multicellular organisms requires the robust establishment of precise proportions between distinct cell-types. This developmental differentiation process typically involves intracellular regulatory and stochastic mechanisms to generate cell-fate diversity as well as intercellular mechanisms to coordinate cell-fate decisions at tissue level. We thus surmise that key insights about the developmental regulation of cell-type proportion can be captured by the modeling study of clustering dynamics in population of inhibitory-coupled noisy bistable systems. This general class of dynamical system is shown to exhibit a very stable two-cluster state, but also frustrated relaxation, collective oscillations or steady-state hopping which prevents from timely and reliably reaching a robust and well-proportioned clustered state. To circumvent these obstacles or to avoid fine-tuning, we highlight a general strategy based on dual-time positive feedback loops, such as mediated through transcriptional versus epigenetic mechanisms, which improves proportion regulation by coordinating early and flexible lineage priming with late and firm commitment. This result sheds new light on the respective and cooperative roles of multiple regulatory feedback, stochasticity and lateral inhibition in developmental dynamics.