Dynamics of BMP signaling and distribution during zebrafish dorsal-ventral patterning

Abstract

During vertebrate embryogenesis, dorsal-ventral patterning is controlled by the BMP/Chordin activator/inhibitor system. BMP induces ventral fates, whereas Chordin inhibits BMP signaling on the dorsal side. Several theories can explain how the distributions of BMP and Chordin are regulated to achieve patterning, but the assumptions regarding activator/inhibitor diffusion and stability differ between models. Notably, ‘shuttling’ models in which the BMP distribution is modulated by a Chordin-mediated increase in BMP diffusivity have gained recent prominence. Here, we directly test five major models by measuring the biophysical properties of fluorescently tagged BMP2b and Chordin in zebrafish embryos. We found that BMP2b and Chordin diffuse and rapidly form extracellular protein gradients, Chordin does not modulate the diffusivity or distribution of BMP2b, and Chordin is not required to establish peak levels of BMP signaling. Our findings challenge current self-regulating reaction-diffusion and shuttling models and provide support for a graded source-sink mechanism underlying zebrafish dorsal-ventral patterning.

Evaluation of BMP-mediated patterning in a 3D mathematical model of the zebrafish blastula embryo

“…The current best fit parameter set is a Chd dominant model, where the production rate of Chd ( ) is much higher than the Nog production rate ( ). Thus, the WT model sensitivity shows that Chd dominates the sharp BMP gradient profile rather than Nog, consistent with previous 1D modeling results (Zinski et al 2017 Since the decay rates and diffusivities of BMP and Chd are fixed based on measurements (Pomreinke et al 2017;Zinski et al 2017), the local sensitivity for the decay rates and diffusivities of Nog, BMP-Chd complex, and BMP-Nog complex are compared in Figure 4B and 4C. The model shows limited sensitivity to the decay rate of BMP-Chd.…”

“…Each parameter combination was then re-simulated without Chordin to predict the BMP signaling gradient in a chordin loss-of-function (LOF) scenario. Based on previous studies (Pomreinke et al 2017;Zinski et al 2017), the diffusion rate and decay of BMP ligand and Chd are fixed as constant, and for BMP, and and for Chd, respectively. The parameter space for the rest of unknown parameters consist of the range used in Zinski et al's study (see Table 2).…”

Transcriptomics reveals complex kinetics of dorsal–ventral patterning gene expression in the mandibular arch

“…We also note the gradually declining expression of grem2b: a secreted dorsal Bmp signaling inhibitor, which is upregulated by both Edn1 and Jag/Notch, and downregulated by Bmp signaling . These results add a new level of temporal complexity to our computational models for the zebrafish D-V arch GRN (Clouthier et al, 2010;Meinecke et al, 2018) similar to models in other patterning systems (Pomreinke et al, 2017;Sagner & Briscoe, 2017;Zinski et al, 2017) particularly for processes involving multiple signals in concert (Zagorski et al, 2017). Testing how combinatorial signals lead to such temporal expression kinetics will require experimental manipulation of morphogen gradients at specific times and locations such as with heat-shock inducible transgenic constructs Zuniga et al, 2011).…”

“…Examples include the interaction of Bmp and Shh signaling in D-V neural tube patterning (Liem, Jessell, & Briscoe, 2000;Zagorski et al, 2017) and the interaction of Wnt, retinoic acid (RA) and Fgf signaling in A-P body axis patterning (McGrew, Hoppler, & Moon, 1997;White, Nie, Lander, & Schilling, 2007). Measurements of morphogen diffusion and immediate downstream target genes, combined with computational modeling, have clarified which of several alternative models of signaling are applicable, such as a source-sink model for early embryonic patterning in zebrafish by the Bmp pathway (Pomreinke et al, 2017;Zinski et al, 2017). Precise measurements of target gene expression, such as those in the Nodal signaling pathway, have also suggested that in some morphogen systems the kinetics of expression are more important than more classical threshold models for proper patterning (Dubrulle et al, 2015).…”

BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids

“…2Avi-x, B). The limited rate of BMP proteins diffusion could participate to this spatial restriction (Kicheva et al, 2007;Pomreinke et al, 2017;Zinski et al, 2017). Alternatively, the formation of an extracellular matrix separating an outer epithelium from inner epithelia within the organoid may act as a barrier hampering BMP4 diffusion (Hu et al, 2004;Ma et al, 2017;Perrimon et al, 2012;Plouhinec et al, 2013;Ramirez and Rifkin, 2009;Wang et al, 2008) (Fig.…”