Generation of extracellular morphogen gradients: the case for diffusion

Stapornwongkul, Kristina S.; Vincent, Jean‐Paul

doi:10.1038/s41576-021-00342-y

Cited by 94 publications

(100 citation statements)

References 279 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Developing embryos often transmit instructions using morphogens, diffusible signaling molecules that induce concentration-dependent responses in target cells. In the most common conception of morphogen function, ligands spread from a localized source to form a concentration gradient ( Lander, 2007 ; Müller et al, 2013 ; Stapornwongkul and Vincent, 2021 ). Cells within the gradient infer their position by sensing the local ligand concentration and initiate a position-appropriate gene expression program ( Rogers and Schier, 2011 ; Stumpf, 1966 ; Wolpert, 1969 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Lord

Carte

Abitua

et al. 2021

eLife

View full text Add to dashboard Cite

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 and relay, 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 activity spreads 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 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 sensitization of responding cells.

show abstract

Section: Introductionmentioning

confidence: 99%

“…Diffusion plays a central role in classical models of morphogen gradient formation ( Müller et al, 2013 ; Stapornwongkul and Vincent, 2021 ). Ligand diffusion from a localized source is sufficient to create a concentration gradient that expands outward over time ( Berg, 1993 ).…”

Section: Introductionmentioning

confidence: 99%

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

Lord

Carte

Abitua

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…Diffusion models of morphogen gradient formation are based on the idea that producing cells create a pool of secreted, extracellular signaling protein whose distributions are determined by interactions with extracellular components that non-producing cells contribute -such as receptors, ECM proteins, and negative regulators that absorb or bind passively diffusing protein (Madamanchi et al, 2021;Stapornwongkul and Vincent, 2021). Although these models assume that morphogen proteins are released constitutively from producing cells, our findings that the amount of signaling protein in a target field is a small fraction of the amount produced and is not proportional to production, do not explicitly invalidate them.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of morphogen proteins expressed at physiological levels and in normal conditions that have been interpreted as supporting diffusion-based dissemination have used methods that do not distinguish cell-free protein from cell-bound protein. In addition, these studies have not been carried out in conditions in which cytonemes could be imaged (Stapornwongkul and Vincent, 2021).…”

Section: Discussionmentioning

confidence: 99%

Regulated delivery controls Drosophila Hedgehog, Wingless, and Decapentaplegic signaling

Hatori

Wood

Barbosa

et al. 2021

eLife

View full text Add to dashboard Cite

Morphogen signaling proteins disperse across tissues to activate signal transduction in target cells. We investigated dispersion of Hedgehog (Hh), Wnt homolog Wingless (Wg), and Bone morphogenic protein homolog Decapentaplegic (Dpp) in the Drosophila wing imaginal disc. We discovered that delivery of Hh, Wg, and Dpp to their respective targets is regulated. We found that <5% of Hh and <25% of Wg are taken up by disc cells and activate signaling. The amount of morphogen that is taken up and initiates signaling did not change when the level of morphogen expression was varied between 50-200% (Hh) or 50-350% (Wg). Similar properties were observed for Dpp. We analyzed an area of 150 mm x 150 mm that includes Hh-responding cells of the disc as well as overlying tracheal cells and myoblasts that are also activated by disc-produced Hh. We found that the extent of signaling in the disc was unaffected by the presence or absence of the tracheal and myoblast cells, suggesting that the mechanism that disperses Hh specifies its destinations to particular cells, and that target cells do not take up Hh from a common pool.

show abstract

“…Dynamic changes in signalling can also occur upon changes in the levels of signalling molecules surrounding a cell, for instance when a cell moves through a spatial gradient of signalling molecules. Such gradients, also termed morphogen gradients, have been shown to organize the embryo into its anteroposterior (head to tail), dorsoventral (back to front), proximodistal and left-right axes [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Signalling dynamics in embryonic development

Sonnen

Janda

2021

Biochemical Journal

View full text Add to dashboard Cite

In multicellular organisms, cellular behaviour is tightly regulated to allow proper embryonic development and maintenance of adult tissue. A critical component in this control is the communication between cells via signalling pathways, as errors in intercellular communication can induce developmental defects or diseases such as cancer. It has become clear over the last years that signalling is not static but varies in activity over time. Feedback mechanisms present in every signalling pathway lead to diverse dynamic phenotypes, such as transient activation, signal ramping or oscillations, occurring in a cell type- and stage-dependent manner. In cells, such dynamics can exert various functions that allow organisms to develop in a robust and reproducible way. Here, we focus on Erk, Wnt and Notch signalling pathways, which are dynamic in several tissue types and organisms, including the periodic segmentation of vertebrate embryos, and are often dysregulated in cancer. We will discuss how biochemical processes influence their dynamics and how these impact on cellular behaviour within multicellular systems.

show abstract

Generation of extracellular morphogen gradients: the case for diffusion

Cited by 94 publications

References 279 publications

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

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

Regulated delivery controls Drosophila Hedgehog, Wingless, and Decapentaplegic signaling

Signalling dynamics in embryonic development

Contact Info

Product

Resources

About