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bioRxiv · 10.1101/2024.06.07.597881

mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation

Tong, L.·Batool, F.·Chiu, Y.-H.·Zhou, Y.·Ma, X.·Atanur, S.·Cui, W.
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Abstract

The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but its underlying molecular mechanisms remain unclear. Here we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the Rho/Rac signaling dynamics and reduces cell adhesion. Despite this, mTORC2-deficient hESCs maintain self-renewal and expression of pluripotent markers when cultured in mouse-embryonic fibroblast conditioned medium supplemented with bFGF (MEF-CM). However, these hESCs exhibit significantly impaired mesoderm and endoderm differentiation in response to BMP4 and Activin, respectively, due to reduced WNT activation mediated by cell-cell interactions. Direct activation of the WNT pathway by a GSK3 inhibitor restores mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a novel mechanism by which mTORC2 regulates cell fate determination and highlights a critical link between the intercellular adhesion and the activation of canonical WNT genes.

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Tong, L., Batool, F., Chiu, Y.-H., Zhou, Y., Ma, X., Atanur, S., Cui, W.. 2024-06-07. mTORC2-mediated cell-cell interaction promote BMP4-induced WNT activation and mesoderm differentiation. https://doi.org/10.1101/2024.06.07.597881

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