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Updated: Jun 12, 2025

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Axin1 and Axin2 regulate the WNT-signaling landscape to promote distinct mesoderm programs

Rocío Hernández-Martínez1, Sonja Nowotschin1, Luke T G Harland2,3

  • 1Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Biorxiv : the Preprint Server for Biology
|September 24, 2024
PubMed

Insights

WNT signaling, regulated by AXIN proteins, guides mesodermal lineage specification during embryonic development. This pathway controls differentiation from pluripotent epiblast cells into various mesodermal fates.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Genetics

Background:

  • Mesodermal lineage specification from pluripotent epiblast during gastrulation remains incompletely understood.
  • WNT/β-catenin signaling is crucial for embryonic development, but its precise roles in mesodermal fate determination require further elucidation.
  • AXIN proteins act as negative regulators of the WNT/β-catenin pathway.

Purpose of the Study:

  • To investigate the role of WNT signaling, particularly in conjunction with AXIN, in the specification of distinct mesodermal lineages.
  • To dissect the regulatory mechanisms governing mesodermal fate determination during gastrulation.
  • To understand how WNT signaling levels are spatially and temporally controlled to prevent aberrant differentiation.

Main Methods:

  • Analysis of Axin1;Axin2 compound mutant mouse embryos.
  • Single-cell and single-embryo transcriptomics.
  • In vitro differentiation assays using pluripotent Epiblast-Like Cells.

Main Results:

  • WNT signaling initiates primitive streak cell differentiation into mesoderm progenitors.
  • WNT signaling cooperates with BMP/pSMAD1/5/9 and NODAL/pSMAD2/3 pathways to specify posterior and anterior mesodermal derivatives, respectively.
  • AXIN1 and AXIN2 spatially and temporally regulate WNT signaling to prevent aberrant mesodermal differentiation from the epiblast.

Conclusions:

  • WNT signaling plays a dual role in mesodermal development: initiating differentiation and subsequently amplifying lineage specification.
  • AXIN proteins are critical for maintaining appropriate WNT signaling levels, ensuring proper mesodermal fate determination.
  • This study reveals a novel regulatory mechanism for mesodermal lineage diversification during gastrulation.
Keywords:
Axin1Axin2BMP/pSMAD1/5/9NODAL/pSMAD2/3WNT signalingembryonicextraembryonicgastrulationmesodermmouse embryo

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