CRB2 fine-tunes F-actin architecture to expand potential in mouse embryonic stem cells

Polarity proteins are involved in establishing the intracellular spatial order to define cellular identity and mediate its plasticity in development, repair, and migration. However, its precise role in pluripotency transition and totipotency remains understood. Here, we showed that Crumbs homologue 2 (CRB2), a typical member of CRUMBS protein family orchestrates cell potential extension in mouse embryonic stem cells (mESCs). CRB2 deficiency impairs formation of embryoid bodies and naive to primed transition (NPT) in mESCs. Mechanistically, CRB2 regulates the formation of F-actin branches by modulating the activity of Arp2/3 complex. Furthermore, overexpression of CRB2 confers totipotency on mESCs, enabling the generation of extra-embryonic lineages and the autonomous self-organization of blastoids. Together, these findings demonstrate that a previously unknown role of the polarity protein CRB2 to orchestrate cell fate transition and totipotency in mouse embryonic stem cells by fine-tuning F-actin structure.