PEDF-Rpsa-Itga6 signaling regulates cortical neuronal morphogenesis

Neuromorphological defects underlie neurodevelopmental disorders and functional defects. We identified a function for ribosomal protein SA (Rpsa) in regulating neuromorphogenesis using electroporation to knockdown Rpsa, which results in apical dendrite misorientation, fewer/shorter extensions with decreased arborization, and decreased spine density with altered spine morphology. We investigated Rpsa’s ligand, pigment epithelium-derived factor (PEDF), and interacting partner on the plasma membrane, Integrin subunit α6 (Itga6). Rpsa, PEDF, and Itga6 knockdown cause similar phenotypes, with Rpsa and Itga6 overexpression rescuing morphological defects in PEDF deficient neurons . Additionally, Itga6 overexpression increases and stabilizes Rpsa expression on the plasma membrane by preventing ubiquitination of Rpsa. GCaMP6s was used to functionally analyze Rpsa knockdown via calcium imaging. Rpsa deficient neurons showed less fluctuation in fluorescence intensity, suggesting defective sub-threshold calcium signaling. Our study identifies a role for PEDF-Rpsa-Itga6 signaling in neuromorphogenesis, thus implicating these molecules in the etiology of neurodevelopmental disorders and identifying them as potential therapeutic candidates.