Consecutive waves of NODAL inhibition are required for epiblast patterning
Abstract
The mouse genome encodes two Lefty genes that antagonize NODAL signaling to break symmetry during gastrulation. Despite their central regulatory role, accurately describing and comparing their embryonic function remains unclear. Here, we generated high replicate powered single-cell transcriptional atlases of Lefty1 and Lefty2 mutant embryogenesis to evaluate the effects of perturbed NODAL signaling during gastrulation. We find that both mutants exhibit phenotypes beginning with the earliest primitive streak derivatives, suggesting a sequential shift from anterior Lefty1 to posterior Lefty2-based control that prevents spurious differentiation into extraembryonic and axial mesoendoderm at the cost of embryonic mesoderm and, in the case of Lefty1, rostral forebrain specification. By phasing bulk SMAD2/3 ChIP-seq data into single-cell-resolved descriptions of signal transduction, we identify distinct NODAL-responsive modules that track the context-specific use of this morphogen over gastrulation time. Collectively, our work highlights the potential of single-cell assays to decode how complex differentiation processes resolve morphogen signals in space and time.
Related
- Editorial: Patterning mechanisms in cardiovascular dysfunction: from bench to bedside
- Multiscale spatial analysis implicates chromosomal metaloops in gene patterning across the Drosophila brain
- Patterning human kidney organoids with synthetic Wnt-secreting organizers
- Identification and characterization of two transmembrane proteins required for virulence of Ustilago maydis
- The Wnt co-receptor Arrow-LRP5/6 is required for planar cell polarity establishment in Drosophila
BibTeX
@article{wang2026consecutive,
title = {{Consecutive waves of NODAL inhibition are required for epiblast patterning}},
author = {Minming Wang and Tien-Chi Jason Hou and JoAnne Villagrana and Yusuke Kijima and Nicolas Dias and Roxanna Altus and Martina Brueckner and Tuğçe Aktaş and Kaelyn Sumigray and Helene Kretzmer and Zachary D. Smith},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78248-8},
url = {https://www.nature.com/articles/s41467-026-78248-8},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Consecutive waves of NODAL inhibition are required for epiblast patterning
AU - Minming Wang
AU - Tien-Chi Jason Hou
AU - JoAnne Villagrana
AU - Yusuke Kijima
AU - Nicolas Dias
AU - Roxanna Altus
AU - Martina Brueckner
AU - Tuğçe Aktaş
AU - Kaelyn Sumigray
AU - Helene Kretzmer
AU - Zachary D. Smith
PY - 2026
DA - 2026/10/09
JO - Nature Communications
DO - 10.1038/s41467-026-78248-8
UR - https://www.nature.com/articles/s41467-026-78248-8
AB - The mouse genome encodes two Lefty genes that antagonize NODAL signaling to break symmetry during gastrulation. Despite their central regulatory role, accurately describing and comparing their embryonic function remains unclear. Here, we generated high replicate powered single-cell transcriptional atlases of Lefty1 and Lefty2 mutant embryogenesis to evaluate the effects of perturbed NODAL signaling during gastrulation. We find that both mutants exhibit phenotypes beginning with the earliest primitive streak derivatives, suggesting a sequential shift from anterior Lefty1 to posterior Lefty2-based control that prevents spurious differentiation into extraembryonic and axial mesoendoderm at the cost of embryonic mesoderm and, in the case of Lefty1, rostral forebrain specification. By phasing bulk SMAD2/3 ChIP-seq data into single-cell-resolved descriptions of signal transduction, we identify distinct NODAL-responsive modules that track the context-specific use of this morphogen over gastrulation time. Collectively, our work highlights the potential of single-cell assays to decode how complex differentiation processes resolve morphogen signals in space and time.
SN - 2041-1723
ER -