» Articles » PMID: 33195234

Incoherent Feedforward Regulation Via Sox9 and ERK Underpins Mouse Tracheal Cartilage Development

Overview
Specialty Cell Biology
Date 2020 Nov 16
PMID 33195234
Citations 6
Authors
Affiliations
Soon will be listed here.
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 () and aggrecan (), 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.

Citing Articles

The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect.

Marom R, Song I, Busse E, Washington M, Berrier A, Rossi V J Clin Invest. 2024; 134(15).

PMID: 38885336 PMC: 11290974. DOI: 10.1172/JCI170369.


Live imaging approach of dynamic multicellular responses in ERK signaling during vertebrate tissue development.

Hirashima T Biochem J. 2022; 479(2):129-143.

PMID: 35050327 PMC: 8883488. DOI: 10.1042/BCJ20210557.


BMP4 and Wnt signaling interact to promote mouse tracheal mesenchyme morphogenesis.

Bottasso-Arias N, Leesman L, Burra K, Snowball J, Shah R, Mohanakrishnan M Am J Physiol Lung Cell Mol Physiol. 2021; 322(2):L224-L242.

PMID: 34851738 PMC: 8794023. DOI: 10.1152/ajplung.00255.2021.


Noise suppression in stochastic genetic circuits using PID controllers.

Modi S, Dey S, Singh A PLoS Comput Biol. 2021; 17(7):e1009249.

PMID: 34319990 PMC: 8360635. DOI: 10.1371/journal.pcbi.1009249.


Mammalian tracheal development and reconstruction: insights from in vivo and in vitro studies.

Kishimoto K, Morimoto M Development. 2021; 148(13).

PMID: 34228796 PMC: 8276987. DOI: 10.1242/dev.198192.


References
1.
OConor C, Case N, Guilak F . Mechanical regulation of chondrogenesis. Stem Cell Res Ther. 2013; 4(4):61. PMC: 3707042. DOI: 10.1186/scrt211. View

2.
Bi W, Deng J, Zhang Z, Behringer R, de Crombrugghe B . Sox9 is required for cartilage formation. Nat Genet. 1999; 22(1):85-9. DOI: 10.1038/8792. View

3.
Shen-Orr S, Milo R, Mangan S, Alon U . Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet. 2002; 31(1):64-8. DOI: 10.1038/ng881. View

4.
Kishimoto K, Tamura M, Nishita M, Minami Y, Yamaoka A, Abe T . Synchronized mesenchymal cell polarization and differentiation shape the formation of the murine trachea and esophagus. Nat Commun. 2018; 9(1):2816. PMC: 6053463. DOI: 10.1038/s41467-018-05189-2. View

5.
Nel-Themaat L, Vadakkan T, Wang Y, Dickinson M, Akiyama H, Behringer R . Morphometric analysis of testis cord formation in Sox9-EGFP mice. Dev Dyn. 2009; 238(5):1100-10. PMC: 2838451. DOI: 10.1002/dvdy.21954. View