Regulation of Nodal signaling propagation by receptor interactions and positive feedback
During vertebrate embryogenesis, the germ layers are patterned by secreted Nodal signals. In the classical model, Nodals elicit signaling by binding to a complex comprising Type I/II Activin receptors (Acvr) and the co-receptor Tdgf1. However, it is currently unclear whether receptor binding can also affect the distribution of Nodals themselves through the embryo, and it is unknown which of the putative Acvr paralogs mediate Nodal signaling in zebrafish. Here, we characterize three Type I (Acvr1) and four Type II (Acvr2) homologs and show that - except for Acvr1c - all receptor-encoding transcripts are maternally deposited and present during zebrafish embryogenesis. We generated mutants and used them together with combinatorial morpholino knockdown and CRISPR F0 knockout (KO) approaches to assess compound loss-of-function phenotypes. We discovered that the Acvr2 homologs function partly redundantly and partially independently of Nodal to pattern the early zebrafish embryo, whereas the Type I receptors Acvr1b-a and Acvr1b-b redundantly act as major mediators of Nodal signaling. By combining quantitative analyses with expression manipulations, we found that feedback-regulated Type I receptors and co-receptors can directly influence the diffusion and distribution of Nodals, providing a mechanism for the spatial restriction of Nodal signaling during germ layer patterning.
Figure 1 - Source Data, Figure 2 - Source Data, Figure 2 - Figure Supplement 1 - Source Data, Figure 2 - Figure Supplement 2 - Source Data, Figure 2 - Figure Supplement 3 - Source Data, Figure 3 - Source Data, Figure 3 - Figure Supplement 1 - Source Data, Figure 3 - Figure Supplement 2 - Source Data, Figure 3 - Figure Supplement 3 - Source Data, Figure 4 - Source Data, Figure 4 - Figure Supplement 1 - Source Data, Figure 5 - Source Data, Figure 6 - Source Data, Figure 6 - Figure Supplement 1 - Source Data and Figure 6 - Figure Supplement 2 - Source Data contain the numerical data used to generate the figures.
Baseline_expression_from_transcriptional_profiling_of_zebrafish_developmental_stagesEBI European Nucleotide Archive (accession no: PRJEB7244).
Article and author information
International Max Planck Research School From Molecules to Organisms"" (Graduate Student Fellowship)
- Hannes Preiß
- David Mörsdorf
- Patrick Müller
Max Planck Society (Max Planck Research Group)
- Patrick Müller
European Research Council (Grant agreement No 637840 (QUANTPATTERN))
- Patrick Müller
European Research Council (Grant agreement No 863952 (ACE-OF-SPACE))
- Patrick Müller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All procedures were executed in accordance with the guidelines of the State of Baden-Württemberg and approved by the Regierungspräsidium Tübingen and the Regierungspräsidium Freiburg.
- Lilianna Solnica-Krezel, Washington University School of Medicine, United States
- Received: January 9, 2021
- Accepted: September 19, 2022
- Accepted Manuscript published: September 23, 2022 (version 1)
- Accepted Manuscript updated: October 5, 2022 (version 2)
- Version of Record published: October 27, 2022 (version 3)
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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