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Neuromorphological defects underlie neurodevelopmental disorders and functional defects. We identified a function for ribosomal protein SA (Rpsa) in regulating neuromorphogenesis using in utero 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 in vivo . Additionally, Itga6 overexpression facilitates Rpsa expression on the membrane. GCaMP6s was used to functionally analyze Rpsa knockdown via ex vivo 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. Author Summary Investigating the mechanisms that drive neuromorphogenesis is a crucial step towards understanding normal and disordered brain development. We found that Rpsa signaling, which is facilitated by Rpsa’s ligand PEDF and its plasma membrane interaction partner Itga6, regulates several key aspects of neuronal morphogenesis including dendritogenesis and dendritic spine formation. We also found that PEDF-Rpsa-Itga6 signaling contributes to calcium signaling, which is important for neuronal function. Furthermore, overexpression of Itga6 increased the expression of Rpsa on the plasma membrane, where it binds extracellular ligands, suggesting that Itga6 facilitates Rpsa signaling in this manner. Thus, PEDF, Rpsa, and Itga6 are implicated in the etiology of neurodevelopmental disorders. This work is of particular relevance to Miller-Dieker syndrome. The PEDF gene ( Serpinf1 ) is located within a clinically relevant region of chromosome 17p13.3 that is deleted in Miller-Dieker syndrome patients. Severe lissencephaly, developmental delay, intellectual disability, and seizures are features of Miller-Dieker syndrome. Further investigation of PEDF-Rpsa-Itga6 signaling may increase our understanding of the mechanisms that contribute to MDS pathogenesis.