
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.11.612342
preprint
1
Article
Axin1 and Axin2 regulate the WNT-signaling landscape to promote distinct mesoderm programs
Hernández-Martínez Rocío
Nowotschin Sonja
Harland Luke T.G.
Kuo Ying-Yi
Theeuwes Bart
Göttgens Berthold http://orcid.org/0000-0001-6302-5705

Lacy Elizabeth
Hadjantonakis Anna-Katerina
Anderson Kathryn V.
11 9 2024
2024.09.11.612342https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.11.612342
nihpp-2024.09.11.612342.pdf
ABSTRACT

How distinct mesodermal lineages – extraembryonic, lateral, intermediate, paraxial and axial – are specified from pluripotent epiblast during gastrulation is a longstanding open question. By investigating AXIN, a negative regulator of the WNT/β-catenin pathway, we have uncovered new roles for WNT signaling in the determination of mesodermal fates. We undertook complementary approaches to dissect the role of WNT signaling that augmented a detailed analysis of Axin1 ; Axin2 mutant mouse embryos, including single-cell and single-embryo transcriptomics, with in vitro pluripotent Epiblast-Like Cell differentiation assays. This strategy allowed us to reveal two layers of regulation. First, WNT initiates differentiation of primitive streak cells into mesoderm progenitors, and thereafter, WNT amplifies and cooperates with BMP/pSMAD1/5/9 or NODAL/pSMAD2/3 to propel differentiating mesoderm progenitors into either posterior streak derivatives or anterior streak derivatives, respectively. We propose that Axin1 and Axin2 prevent aberrant differentiation of pluripotent epiblast cells into mesoderm by spatially and temporally regulating WNT signaling levels.
==== Body
pmc
