The scramblases VMP1 and TMEM41B are required for primitive endoderm specification by targeting WNT signaling

The endoplasmic reticulum (ER) is a central hub that integrates lipid metabolism and protein secretion to maintain cellular homeostasis and mediate interactions with the environment. Two ER-resident proteins, VMP1 and TMEM41B, act as scramblases, regulating lipid membrane composition to support critical processes such as autophagy and lipid droplet metabolism. Despite their essential functions in mouse development, the mechanisms by which the loss of either gene leads to embryonic lethality remain unclear.

To investigate their roles in lineage specification and development, the authors generated mutations of Vmp1 and Tmem41b in mouse embryonic stem cells (ESCs). Although the loss of both genes did not impair self-renewal and pluripotency of the mutant ESCs, they exhibited impaired differentiation into the primitive endoderm lineage. In vivo, the primitive endoderm forms extraembryonic membranes that are essential for supporting embryo development. This differentiation defect was linked to dysregulated expression of genes in the WNT signaling pathway and reduced abundance of the WNT receptor FZD2 at the plasma membrane. Notably, transgenic expression of Fzd2 fully rescued the XEN differentiation defect, demonstrating that the absence of VMP1 and TMEM41B disrupts the maturation and stability of the FZD2 receptor, thereby impairing WNT signaling.

In summary, VMP1 and TMEM41B emerge as critical regulators of the secretory machinery. Beyond their established roles in lipid metabolism, the new study reveals their involvement in protein trafficking and cell signaling.

Link to the paper in external page "Cell Death and Differentiation".