Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways

Luca Guglielmi, Claire Heliot, Sunil Kumar, Yuriy Alexandrov, Ilaria Gori, Foteini Papaleonidopoulou, Christopher Barrington, Philip East, Andrew D. Economou, Paul M. W. French, James McGinty and Caroline S. Hill ()
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Luca Guglielmi: The Francis Crick Institute
Claire Heliot: The Francis Crick Institute
Sunil Kumar: The Francis Crick Institute
Yuriy Alexandrov: The Francis Crick Institute
Ilaria Gori: The Francis Crick Institute
Foteini Papaleonidopoulou: The Francis Crick Institute
Christopher Barrington: The Francis Crick Institute
Philip East: The Francis Crick Institute
Andrew D. Economou: The Francis Crick Institute
Paul M. W. French: Imperial College London
James McGinty: Imperial College London
Caroline S. Hill: The Francis Crick Institute

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 in zebrafish and investigated the consequences of this on signaling by the TGF-β family morphogens, BMPs and Nodal. We demonstrate that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling. However, unexpectedly, Nodal signaling is maintained, but lacks robustness. This Smad4-independent Nodal signaling is sufficient for mesoderm specification, but not for optimal endoderm specification. Furthermore, using Optical Projection Tomography in combination with 3D embryo morphometry, we have generated a BMP morphospace and demonstrate that Smad4 mutants are morphologically indistinguishable from embryos in which BMP signaling has been genetically/pharmacologically perturbed. Smad4 is thus differentially required for signaling by different TGF-β family ligands, which has implications for diseases where Smad4 is mutated or deleted.

Date: 2021
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DOI: 10.1038/s41467-021-26486-3

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