Genetic dissection of the role of Piga and Pgap2 in the embryonic mouse brain.

Glycosylphosphatidylinositol (GPI) anchors are a post-translational modification made to over 150 proteins. These GPI-anchored proteins are enriched in lipid rafts in the plasma membrane and serve a variety of functions. Human pathogenic variants in GPI biosynthesis pathway enzymes are collectively called inherited GPI deficiencies and lead to several brain anomalies, but we still lack a deep understanding of GPI-anchor functions in brain development. PIGA and PGAP2 are two enzymes in the GPI-anchor biosynthesis pathway. A Nestin-Cre mediated deletion of Piga in the mouse led to early postnatal death and significant structural brain malformations. There are no studies on Pgap2 loss of function in the brain to date. We extended these studies with a series of genetic ablations to further determine the role of Piga and Pgap2 in the forebrain, oligodendrocytes, and cerebellum. We find Piga expression in the hindbrain is absolutely required for survival while Pgap2 ablations were much less deleterious.