Abstract
Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.
Highlights
The differentiation of biological systems is directed by the interpretation of biochemical morphogen gradients in a concentration-dependent manner
In numerous developmental contexts, TGF-β signaling has a greater response to heterodimeric ligands, as compared to homomeric ligands
We use a biophysically-informed computational modeling approach to investigate the system dynamics of heterodimerheterotetramer Bone Morphogenetic Protein (BMP) signaling, to understand the cause and consequence of the requirement for Bmp2/7-mediated signaling in dorsoventral patterning in zebrafish development
Summary
The differentiation of biological systems is directed by the interpretation of biochemical morphogen gradients in a concentration-dependent manner. The remarkable robustness and precision of developmental patterning reveals careful organization of the underlying developmental signaling systems. These systems are highly evolutionarily conserved, and through the use of mathematical modeling, the foundational principles that guide the evolution of these systems are beginning to be understood. BMP receptors oligomerize, as depicted in Fig 1A and 1B, into tetrameric signaling complexes that consist of two type I and two type II kinase receptors [1,2]. Ligand-bound tetrameric signaling complexes initiate an intracellular signaling cascade by instigating the phosphorylation of BMP-responsive Smad proteins [2,5,6]. The phosphorylated Smad (pSmad) forms complexes with co-Smad and accumulates in the nucleus to regulate gene expression [6]
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