PUBLICATION

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

Authors
Guglielmi, L., Heliot, C., Kumar, S., Alexandrov, Y., Gori, I., Papaleonidopoulou, F., Barrington, C., East, P., Economou, A.D., French, P.M.W., McGinty, J., Hill, C.S.
ID
ZDB-PUB-211106-4
Date
2021
Source
Nature communications   12: 6374 (Journal)
Registered Authors
Hill, Caroline
Keywords
none
Datasets
GEO:GSE162289, GEO:GSE164574
MeSH Terms
  • Animals
  • Bone Morphogenetic Proteins/metabolism*
  • Embryonic Development
  • Endoderm/metabolism
  • Gene Knockout Techniques
  • Mesoderm/metabolism
  • Morphogenesis
  • Nodal Protein/metabolism*
  • Signal Transduction
  • Smad4 Protein/deficiency
  • Smad4 Protein/genetics
  • Smad4 Protein/metabolism*
  • Transforming Growth Factor beta/metabolism*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/growth & development*
  • Zebrafish/metabolism
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
34737283 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping