Wnt/β-catenin signalling modulates the timing of cell fate decision making in the early mouse embryo

Joaquin Lilao-Garzón; Elena Corujo-Simon; Meritxell Vinyoles; Sabine C. Fischer; José Guillén; Tina Balayo; Silvia Muñoz-Descalzo

doi:10.1371/journal.pone.0344295

Wnt/β-catenin signalling modulates the timing of cell fate decision making in the early mouse embryo

Joaquin Lilao-Garzón, Elena Corujo-Simon, Meritxell Vinyoles, Sabine C. Fischer, José Guillén, Tina Balayo, Silvia Muñoz-Descalzo

Research output: Contribution to journal › Article › peer-review

Abstract

Cell fate choice is a key event happening during preimplantation mouse development. From embryonic day 3.5 (E3.5) to E4.5, the inner cell mass (ICM) differentiates into epiblast (Epi, NANOG expressing cells) and primitive endoderm (PrE, GATA6, SOX17 and/or GATA4 expressing cells). The mechanism by which ICM cells differentiate into Epi cells and PrE cells remains partially unknown. FGF/ERK has been proposed as the main signalling pathway for this event, but it does not explain co-expression of NANOG and GATA6 or how the cell fate choice is initiated. In this study, we investigate whether Wnt/β-catenin signalling also plays a role. To this end, we use two in vitro models based on inducible GATA6 expression: one in 2D (flat cultured cells), and another in 3D, namely ICM organoids. By combining these in vitro models with in vivo mouse embryos, chemical and classical genetics, and quantitative 3D immunofluorescence analyses, we propose a dual role for Wnt/β-catenin signalling. We find that β-catenin, acting alongside FGF/ERK signalling, helps to guide the cell fate choice towards PrE. Additionally, by regulating GATA6 and GATA4 stability, Wnt/β-catenin signalling further facilitates this choice. To summarise, we observe that Wnt/β-catenin signalling pathway activation promotes PrE differentiation, while its inhibition delays it.

Original language	English
Article number	e0344295
Journal	PLoS ONE
Volume	21
Issue number	3
Early online date	6 Mar 2026
DOIs	https://doi.org/10.1371/journal.pone.0344295
Publication status	Published - 6 Mar 2026

Data Availability Statement

https://zenodo.org/records/17199526.

Funding

Early work at the University of Bath was supported by a Wellcome Trust Seed Award (109589/Z/15/Z) and ECS funding was provided by the University of Bath. At the ULPGC, work at SMDlab was funded by the ACIISI (CEI2019-02), Programa de Ayudas a la Investigación de la ULPGC, and ACIISI co-funded by FEDER Funds (ProID2020010013). JLG was supported by the ULPGC predoctoral program and SMD was supported by the ‘‘Viera y Clavijo’’ Program from the ACIISI, and the ULPGC. Imaging at the IUIBS was done at the SIMACE (Servicio de Investigación en Microscopía Avanzada Confocal y Electrónica). Mouse work at the IUIBS was done at the now established SABiA (Servicio de Animalario y Bienestar Animal). TB was funded by a “Ayuda para Personal Técnico de Apoyo” from the Ministerio de Economía Industria y Competitividad (PTA2017-14230-I). Work at the SCF lab was supported through funding by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project number 470129398 and start-up funding by the University of Wuerzburg. MV funding was provided by EMBO Postdoctoral fellowships (ALTF 509-2015).

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abstract = "Cell fate choice is a key event happening during preimplantation mouse development. From embryonic day 3.5 (E3.5) to E4.5, the inner cell mass (ICM) differentiates into epiblast (Epi, NANOG expressing cells) and primitive endoderm (PrE, GATA6, SOX17 and/or GATA4 expressing cells). The mechanism by which ICM cells differentiate into Epi cells and PrE cells remains partially unknown. FGF/ERK has been proposed as the main signalling pathway for this event, but it does not explain co-expression of NANOG and GATA6 or how the cell fate choice is initiated. In this study, we investigate whether Wnt/β-catenin signalling also plays a role. To this end, we use two in vitro models based on inducible GATA6 expression: one in 2D (flat cultured cells), and another in 3D, namely ICM organoids. By combining these in vitro models with in vivo mouse embryos, chemical and classical genetics, and quantitative 3D immunofluorescence analyses, we propose a dual role for Wnt/β-catenin signalling. We find that β-catenin, acting alongside FGF/ERK signalling, helps to guide the cell fate choice towards PrE. Additionally, by regulating GATA6 and GATA4 stability, Wnt/β-catenin signalling further facilitates this choice. To summarise, we observe that Wnt/β-catenin signalling pathway activation promotes PrE differentiation, while its inhibition delays it.",

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Wnt/β-catenin signalling modulates the timing of cell fate decision making in the early mouse embryo

Abstract

Data Availability Statement

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