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

Abstract

The mechanistic target of rapamycin complex 2 (mTORC2) is essential for embryonic development but the underlying molecular mechanisms remain unclear. Here we show that disruption of mTORC2 in human embryonic stem cells (hESCs) considerably alters the balance of Rho/Rac signaling and reduces cell adhesion. Although these changes have no clear effect on hESC self-renewal and the expression of pluripotent markers, they significantly avert BMP-induced activation of canonical WNT genes, leading to impaired mesendoderm differentiation. Direct activation of downstream WNT pathway by inhibiting GSK3 dramatically improves mesendoderm differentiation in mTORC2-deficient hESCs. Our study uncovers a new mechanism by which mTORC2 regulates cell fate determination and, more importantly, link the intercellular contacts with the activation of the WNT genes.