Neural stem cell-specific deficiency of (pro)renin receptor causes brain malformation and perinatal lethality in mice.

Abstract

(Pro)renin receptor [(P)RR], encoded by Atp6ap2, is a transmembrane protein found in many organs. It functions in lysosomes as part of the vacuolar-ATPase complex, facilitating autophagy and degradation. Mutations in ATP6AP2 are linked to neurological conditions, including X-linked parkinsonism with spasticity. However, our understanding of the role of (P)RR in whole brain development remains incomplete. Here, we generated mice with neural stem cell (NSC)-specific (P)RR deficiency (CKO). CKO mice exhibited significant brain atrophy during mid-gestation, leading to perinatal lethality. Fetal CKO brains showed lateral ventricular enlargement with malformation of neocortex and ganglionic eminence (GE) from mid-gestation. CKO brains showed massive apoptosis in multiple regions along with microglial activation at E15. On the contrary, CKO NSCs showed normal self-renewal ability, suggesting that (P)RR is critical for survival of differentiated cells. In line with this, the mechanistic study using RNA-seq of primary NSCs revealed downregulation of genes related to neurodevelopment and myelination. We also found p62 and LC3-II protein accumulation, hallmarks of deregulated autophagic pathways, in CKO fetal brains and NSCs. These findings demonstrate that (P)RR is crucial for guiding NSC differentiation and ensuring the coordinated construction of brain architecture during development.