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MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback.

ABSTRACT: Positive feedback driven by transcriptional regulation has long been considered a key mechanism underlying cell lineage segregation during embryogenesis. Using the developing spinal cord as a paradigm, we found that canonical, transcription-driven feedback cannot explain robust lineage segregation of motor neuron subtypes marked by two cardinal factors, Hoxa5 and Hoxc8. We propose a feedback mechanism involving elementary microRNA-mRNA reaction circuits that differ from known feedback loop-like structures. Strikingly, we show that a wide range of biologically plausible post-transcriptional regulatory parameters are sufficient to generate bistable switches, a hallmark of positive feedback. Through mathematical analysis, we explain intuitively the hidden source of this feedback. Using embryonic stem cell differentiation and mouse genetics, we corroborate that microRNA-mRNA circuits govern tissue boundaries and hysteresis upon motor neuron differentiation with respect to transient morphogen signals. Our findings reveal a previously underappreciated feedback mechanism that may have widespread functions in cell fate decisions and tissue patterning.

SUBMITTER: Li CJ

PROVIDER: S-EPMC8062999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.

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MicroRNA governs bistable cell differentiation and lineage segregation via a noncanonical feedback.

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