Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification.

The endoplasmic reticulum (ER) is a central hub for lipid metabolism and protein secretion, crucial for maintaining cellular homeostasis and mediating environmental interactions. ER-resident proteins VMP1 and TMEM41B function as scramblases, regulating lipid membranes to support macroautophagy and lipid droplet metabolism. To explore their developmental roles, we generated and mutations in mouse embryonic stem cells (ESCs). While these mutations did not affect ESC self-renewal or pluripotency, they impaired differentiation into the primitive endoderm lineage. Our findings reveal that this defect stems from VMP1 and TMEM41B's critical role in the maturation and stability of FZD2/FRIZZLED2, essential for WNT signaling. Thus, this study highlights their extensive role in protein trafficking, linking lipid metabolism to cell signaling and deepening our understanding of their diverse contributions to cellular and developmental processes.