The pattern of Nodal morphogen signaling is shaped by co-receptor expression

Abstract

Embryos must communicate instructions to their constituent cells over long distances. These instructions are often encoded in the concentration of signals called morphogens. In the textbook view, morphogen molecules diffuse from a localized source to form a concentration gradient, and target cells adopt fates by measuring the local morphogen concentration. However, natural patterning systems often incorporate numerous co-factors and extensive signaling feedback, suggesting that embryos require additional mechanisms to generate signaling patterns. Here, we examine the mechanisms of signaling pattern formation for the mesendoderm inducer Nodal during zebrafish embryogenesis. We find that Nodal signaling activity spans a normal range in the absence of signaling feedback, suggesting that diffusion is sufficient for Nodal gradient formation. We further show that the range of endogenous Nodal ligands is set by the EGF-CFC co-receptor Oep: in the absence of Oep, Nodal ligands spread to form a nearly uniform distribution throughout the embryo. In turn, increasing Oep levels sensitizes cells to Nodal ligands. We recapitulate these experimental results with a computational model in which Oep regulates the diffusive spread of Nodal ligands by setting the rate of capture by target cells. This model predicts, and we confirm in vivo, the surprising observation that a failure to replenish Oep during patterning transforms the Nodal signaling gradient into a travelling wave. These results reveal that patterns of Nodal morphogen signaling are shaped by co-receptor-mediated restriction of ligand spread and cell sensitization.

Nodal signaling establishes a competency window for stochastic cell fate switching

“…Differences in morphogen levels have generally been considered at the level of broad graded profiles across fields of cells. Indeed, when we and others previously constructed Nodal and Fgf signaling profiles in early zebrafish embryos, we averaged the intensity of immunofluorescence for the signaling readouts P-Smad2 and P-Erk respectively across the multiple cells within each cell tier relative to the margin (Lord et al, 2021; Rogers et al, 2017; van Boxtel et al, 2018). However, it is possible that the heterogeneity seen in the appearance of endodermal progenitor cells could be the result of cell-to-cell differences in the levels of Nodal or Fgf signaling.…”

Wnt3 distribution in the zebrafish brain is determined by expression, diffusion and multiple molecular interactions

“…Apart from the interactions of signaling molecules with the extracellular matrix proteins, the transient trapping of ligands by their receptors also shapes their distribution profile ( Müller et al, 2013 ). For instance, the transient binding of Nodals to their receptor Acvr2b and co-receptor Oep ( Lord et al, 2019 ; Wang et al, 2016 ), Hedgehog to the 12-transmembrane protein Dispatched ( Callejo et al, 2011 ), and Wingless to the Fzd receptor ( Baeg et al, 2004 ) influence their respective distributions and gradient kinetics. Hence, it is critical to evaluate the binding affinity of Wnt3 with its target receptors to understand its signaling range and action.…”

Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids

“…Studies in Zebrafish suggest that the range of Nodal signaling is limited through its capture by the coreceptor Cripto 38 . Although embryos deficient for Cripto cannot signal, Nodal protein from the margin can disperse over a much wider range than in wildtype embryos.…”