Sharp Developmental Thresholds Defined Through Bistability By Antagonistic Gradients of Retinoic Acid and FGF Signaling
Camille
Nicodemus
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model runs in OpenCell and COR. It was created from equations [1] to [5], and [12] and [13]. The model parameters were taken from the caption of Figure 3. The CellML model cannot recreate the figures from the paper due to constant values for the parameters K_I and K_A. The units have been checked and they are consistent.
Model Structure
ABSTRACT: The establishment of thresholds along morphogen gradients in the embryo is poorly understood. Using mathematical modeling, we show that mutually inhibitory gradients can generate and position sharp morphogen thresholds in the embryonic space. Taking vertebrate segmentation as a paradigm, we demonstrate that the antagonistic gradients of retinoic acid (RA) and Fibroblast Growth Factor (FGF) along the presomitic mesoderm (PSM) may lead to the coexistence of two stable steady states. Here, we propose that this bistability is associated with abrupt switches in the levels of FGF and RA signaling, which permit the synchronized activation of segmentation genes, such as mesp2, in successive cohorts of PSM cells in response to the segmentation clock, thereby defining the future segments. Bistability resulting from mutual inhibition of RA and FGF provides a molecular mechanism for the all-or-none transitions assumed in the "clock and wavefront" somitogenesis model. Given that mutually antagonistic signaling gradients are common in development, such bistable switches could represent an important principle underlying embryonic patterning.
The original paper reference is cited below:
Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling. Goldbeter A, Gonze D, Pourquie O. 2007, Developmental Dynamics, 236, 1495-1508. PubMed ID: 17497689
reaction diagram
Scheme of the regulatory interactions between RA and FGF signaling. Synthesis of RA is catalyzed by the enzyme RALDH2, while RA is hydrolyzed by the enzyme CYP26. The inhibitory effect exerted on RA by FGF arises from the induction of cyp26 expression by FGF. The inhibition exerted by RA on FGF occurs through impeding the rate of fgf8 mRNA translation. As shown by the model built according to this regulatory scheme, bistability readily arises from the mutual inhibition between RA and FGF.
$\frac{d \mathrm{RA}}{d \mathrm{time}}=\mathrm{v\_s1}-\mathrm{k\_d1}C\mathrm{RA}-\mathrm{k\_d5}\mathrm{RA}$
$\frac{d \mathrm{M\_C}}{d \mathrm{time}}=\mathrm{V\_0}+\frac{\mathrm{V\_sC}F^{n}}{\mathrm{K\_A}^{n}+F^{n}}-\mathrm{k\_d3}\mathrm{M\_C}$
$\frac{d C}{d \mathrm{time}}=\mathrm{k\_s2}\mathrm{M\_C}-\mathrm{k\_d2}C$
$\frac{d F}{d \mathrm{time}}=\frac{\mathrm{k\_s3}\mathrm{M\_F}\mathrm{K\_I}^{m}}{\mathrm{K\_I}^{m}+\mathrm{RA}^{m}}-\mathrm{k\_d4}F$
$\mathrm{v\_s1}=\mathrm{k\_s1}\mathrm{RALDH2\_0}(1-\frac{x}{L})$
$\mathrm{M\_F}=\frac{\mathrm{M\_0}x}{L}$
$\mathrm{alpha\_1}=\frac{\mathrm{RA}}{\mathrm{RA}+\mathrm{K\_r1}}$
$\mathrm{alpha\_2}=\frac{F}{F+\mathrm{K\_r2}}$
$\mathrm{rho}=\frac{\mathrm{alpha\_2}}{\mathrm{alpha\_1}}$
Nicodemus
Camille
Emily
cnic041@aucklanduni.ac.nz
The University of Auckland
Auckland Bioengineering Institute
2010-11-16
keyword
signal transduction
bistability
FGF
17497689
Goldbeter
A
Gonze
D
Pourquie
O
Sharp Developmental Thresholds Defined Through Bistability By Antagonistic Gradients of Retinoic Acid and FGF Signaling
2007-06
Developmental Dynamics
236
1495
1508