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Title: Incoherent Feedforward Regulation via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development
Authors: Yoshida, Takuya
Matsuda, Michiyuki  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-5876-9969 (unconfirmed)
Hirashima, Tsuyoshi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-7323-9627 (unconfirmed)
Author's alias: 松田, 道行
平島, 剛志
Keywords: chondrogenesis
FRET imaging
incoherent feedforward loop
mathematical model
MAP kinase/ERK
SOX9
trachea
Issue Date: 22-Oct-2020
Publisher: Frontiers Media SA
Journal title: Frontiers in Cell and Developmental Biology
Volume: 8
Thesis number: 585640
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.
Rights: © 2020 Yoshida, Matsuda and Hirashima. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
URI: http://hdl.handle.net/2433/262257
DOI(Published Version): 10.3389/fcell.2020.585640
PubMed ID: 33195234
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