Dataset Information

Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development.

ABSTRACT: Tracheal cartilage provides architectural integrity to the respiratory airway, and defects in this structure during embryonic development cause severe congenital anomalies. Previous genetic studies have revealed genes that are critical for the development of tracheal cartilage. However, it is still unclear how crosstalk between these proteins regulates tracheal cartilage formation. Here we show a core regulatory network underlying murine tracheal chondrogenesis from embryonic day (E) 12.5 to E15.5, by combining volumetric imaging of fluorescence reporters, inhibitor assays, and mathematical modeling. We focused on SRY-box transcription factor 9 (Sox9) and extracellular signal-regulated kinase (ERK) in the tracheal mesenchyme, and observed a synchronous, inverted U-shaped temporal change in both Sox9 expression and ERK activity with a peak at E14.5, whereas the expression level of downstream cartilage matrix genes, such as collagen II alpha 1 (Col2a1) and aggrecan (Agc1), monotonically increased. Inhibitor assays revealed that the ERK signaling pathway functions as an inhibitory regulator of tracheal cartilage differentiation during this period. These results suggest that expression of the cartilage matrix genes is controlled by an incoherent feedforward loop via Sox9 and ERK, which is supported by a mathematical model. Furthermore, the modeling analysis suggests that a Sox9-ERK incoherent feedforward regulation augments the robustness against the variation of upstream factors. The present study provides a better understanding of the regulatory network underlying the tracheal development and will be helpful for efficient induction of tracheal organoids.

SUBMITTER: Yoshida T

PROVIDER: S-EPMC7642454 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development.

Yoshida Takuya T Matsuda Michiyuki M Hirashima Tsuyoshi T

Frontiers in cell and developmental biology 20201022

Tracheal cartilage provides architectural integrity to the respiratory airway, and defects in this structure during embryonic development cause severe congenital anomalies. Previous genetic studies have revealed genes that are critical for the development of tracheal cartilage. However, it is still unclear how crosstalk between these proteins regulates tracheal cartilage formation. Here we show a core regulatory network underlying murine tracheal chondrogenesis from embryonic day (E) 12.5 to E15 ...[more]

PMID: 33195234

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Project description:BackgroundRegulation of gene expression is of paramount importance in all living systems. In the past two decades, it has been discovered that certain motifs, such as the feedforward motif, are overrepresented in gene regulatory circuits. Feedforward loops are also ubiquitous in process control engineering, and are nearly always structured so that one branch has the opposite effect of the other, which is a structure known as an "incoherent" feedforward loop in biology. In engineered systems, feedforward control loops are subject to several engineering constraints, including that (1) they are finely-tuned so that the system returns to the original steady state after a disturbance occurs (perfect adaptation), (2) they are typically only implemented in the combination with negative feedback, and (3) they can greatly improve the stability and dynamical characteristics of the conjoined negative feedback loop. On the other hand, in biology, incoherent feedforward loops can serve many purposes, one of which may be perfect adaptation. It is an open question as to whether those that achieve perfect adaptation are subject to the above engineering principles.ResultsWe analyzed an incoherent feedforward gene regulatory motif from the standpoint of the above engineering principles. In particular, we showed that an incoherent feedforward loop Type 1 (I1-FFL), from within a gene regulatory circuit, can be finely-tuned for perfect adaptation after a stimulus, and that the robustness of this behavior is increased by the presence of moderate negative feedback. In addition, we analyzed the advantages of adding a feedforward loop to a system that already operated under negative feedback, and found that the dynamical properties of the combined feedforward/feedback system were superior.ConclusionsOur analysis shows that many of the engineering principles used in engineering design of feedforward control are also applicable to feedforward loops in biological systems. We speculate that principles found in other domains of engineering may also be applicable to analogous structures in biology.

Dataset Information

Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development.

Publications

Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development.

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