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

  1. Nathan D Lord  Is a corresponding author
  2. Adam N Carte
  3. Philip B Abitua
  4. Alexander F Schier  Is a corresponding author
  1. University of Pittsburgh School of Medicine, United States
  2. Harvard University, Switzerland
  3. Harvard University, United States
  4. University of Basel, Switzerland


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.

Data availability

Source data files have been provided for all quantified immunofluorescence datasets.

Article and author information

Author details

  1. Nathan D Lord

    Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9553-2779
  2. Adam N Carte

    Systems Biology/Molecular and Cellular Biology, Harvard University, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3791-4872
  3. Philip B Abitua

    Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexander F Schier

    University of Basel, Basel, Switzerland
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.


National Institutes of Health (K99-HD097297-01)

  • Nathan D Lord

National Institutes of Health (R37GM056211)

  • Alexander F Schier

National Institutes of Health (T32GM080177)

  • Adam N Carte

National Science Foundation (DGE1745303)

  • Adam N Carte

Arnold and Mabel Beckman Foundation

  • Nathan D Lord

Damon Runyon Cancer Research Foundation

  • Philip B Abitua

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lilianna Solnica-Krezel, Washington University School of Medicine, United States


Animal experimentation: All vertebrate animal work was performed at the facilities of Harvard University, Faculty of Arts & Sciences (HU/FAS). The HU/FAS animal care and use program maintains full AAALAC accreditation, is assured with OLAW (A3593-01), and is currently registered with the USDA. This study was approved by the Harvard University/Faculty of Arts & Sciences Standing Committee on the Use of Animals in Research & Teaching under Protocol No. 25-08.

Version history

  1. Received: January 5, 2020
  2. Accepted: May 26, 2021
  3. Accepted Manuscript published: May 26, 2021 (version 1)
  4. Version of Record published: July 8, 2021 (version 2)


© 2021, Lord et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.


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  1. Nathan D Lord
  2. Adam N Carte
  3. Philip B Abitua
  4. Alexander F Schier
The pattern of Nodal morphogen signaling is shaped by co-receptor expression
eLife 10:e54894.

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