On the conflict between precision and robustness in the proportion regulation of cell types

TL;DR

This paper explores the inherent trade-off between the precision of cell type proportion regulation and the robustness of cell differentiation, using a model based on feedback mechanisms in Dictyostelium discoideum.

Contribution

It introduces a novel model combining global negative feedback and cell-autonomous positive feedback to explain imprecise proportion regulation.

Findings

Regulation controls proportions within thresholds but not precisely within a range.

Bistability leads to a span of cell-type proportions.

A fundamental conflict exists between regulation precision and differentiation robustness.

Abstract

In Dictyostelium discoideum the proportion of cell types is known to be actively regulated, recovering, for example, after the removal of a given cell type. However, we have recently shown that regulation is intrinsically imprecise: it controls the proportion above/below certain upper and lower thresholds, but not within an allowed range of values that these thresholds define. To explain this finding we present a model based on (i) a global negative feedback, and (ii) a cell-autonomous positive feedback leading to a hysteresis-like behaviour (i.e, a bistability of cell type). The simulated cell-type proportion is indeed found to span a range of values as a consequence of the bistability. We conclude that there is a general conflict between the precision of proportion regulation and the robustness of the differentiation of cell types.