The BMP signaling gradient is interpreted through concentration thresholds in dorsal–ventral axial patterning

Abstract

Bone Morphogenetic Protein (BMP) patterns the dorsal–ventral (DV) embryonic axis in all vertebrates, but it is unknown how cells along the DV axis interpret and translate the gradient of BMP signaling into differential gene activation that will give rise to distinct cell fates. To determine the mechanism of BMP morphogen interpretation in the zebrafish gastrula, we identified 57 genes that are directly activated by BMP signaling. By using Seurat analysis of single-cell RNA sequencing (scRNA-seq) data, we found that these genes are expressed in at least 3 distinct DV domains of the embryo. We distinguished between 3 models of BMP signal interpretation in which cells activate distinct gene expression through interpretation of thresholds of (1) the BMP signaling gradient slope; (2) the BMP signal duration; or (3) the level of BMP signal activation. We tested these 3 models using quantitative measurements of phosphorylated Smad5 (pSmad5) and by examining the spatial relationship between BMP signaling and activation of different target genes at single-cell resolution across the embryo. We found that BMP signaling gradient slope or BMP exposure duration did not account for the differential target gene expression domains. Instead, we show that cells respond to 3 distinct levels of BMP signaling activity to activate and position target gene expression. Together, we demonstrate that distinct pSmad5 threshold levels activate spatially distinct target genes to pattern the DV axis.

The mutual repression between Pax2 and Snail factors regulates the epithelial/mesenchymal state during intermediate mesoderm differentiation

“…S5). This is consistent with the gradient of BMP signalling in patterning the mesoderm along the mediolateral axis in the chick embryo among other vertebrates (James and Schultheiss, 2005) and with recent data showing that the embryo interprets Bmp7 concentrations thresholds (Greenfeld et al, 2021). Thus, Bmp7 induces pronephros differentiation through two independent mechanisms, by repressing an EMT inducer, Snail1 , and by inducing a MET inducer, Pax2 in the intermediate mesoderm.…”

Inference of Morphogen Gradient Precision from Molecular Noise Data

“…More than 50 years since the publication of the French flag model [11], it remains a matter of debate how morphogen gradients are read out [35]. Recent experiments support a thresholdbased readout of the BMP gradient along the zebrafish dorsalventral axis [36]. Our finding that single noisy gradients provide a much more robust positional patterning mechanism than previously appreciated resolves the long-standing conundrum of how the observed patterning precision can be achieved with a simple threshold-based readout of a single gradient.…”

The Role of BMP Signaling in Female Reproductive System Development and Function

“…These are important morphogens that play a key role during embryonic development and maintenance of adult tissue homeostasis. BMPs form a concentration gradient that activates differential genes that will give rise to distinct cell fates during dorsal–ventral (DV) axis patterning [ 20 ]. Different processes in early development are dependent on BMP signaling for the regulation of cell proliferation, differentiation, migration, organization, and apoptosis [ 18 , 21 , 22 ].…”