regulates pial basement membrane (BM) organization during cortical development. Disruption of the Gpr56 gene in mice leads to neuronal malformation in the cerebral cortex, which resulted in 4 critical pathological morphologies: defective pial BM, abnormal localized radial glial endfeet, malpositioned Cajal-Retzius cells, and overmigrated neurons. Furthermore, the interaction of GPR56 and collagen III inhibits neural migration to regulate lamination of the cerebral cortex. Next to GPR56, the α3β1 integrin is also involved in pial BM maintenance. Study from Itga3 (α3 integrin)/Gpr56 double knockout mice showed increased neuronal overmigration compared to Gpr56 single knockout mice, indicating cooperation of GPR56 and α3β1 integrin in modulation of the development of the cerebral cortex. More recently, the Walsh laboratory showed that alternative splicing of GPR56 regulates regional cerebral cortical patterning. In depression patients, blood GPR56 mRNA expression increases only in responders and not non-responders to serotonin-norepinephrine reuptake inhibitor treatment. Furthermore, GPR56 was down-regulated in the prefrontal cortex of individuals with depression that died by suicide. Outside the nervous system, GPR56 has been linked to muscle function and male fertility. The expression of GPR56 is upregulated during early differentiation of human myoblasts. Investigation of Gpr56 knockout mice and BFPP patients showed that GPR56 is required for in vitro myoblast fusion via signaling of serum response factor (SRF) and nuclear factor of activated T-cell (NFAT), but is not essential for muscle development in vivo. Additionally, GPR56 is a transcriptional target of peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 and regulates overload-induced muscle hypertrophy through Gα12/13 and mTOR signaling. Therefore, the study of knockout mice revealed that GPR56 is involved in testis development and male fertility. In melanocytic cells GPR56 gene expression may be regulated by MITF. Mutations in GPR56 cause the brain developmental disorder BFPP, characterized by disordered cortical lamination in frontal cortex. Mice lacking expression of GPR56 develop a comparable phenotype. Furthermore, loss of GPR56 leads to reduced fertility in male mice, resulting from a defect in seminiferous tubule development. GPR56 is expressed in glioblastoma/astrocytoma as well as in esophageal squamous cell, breast, colon, non-small cell lung, ovarian, and pancreatic carcinoma. GPR56 was shown to localize together with α-actinin at the leading edge of membrane filopodia in glioblastoma cells, suggesting a role in cell adhesion/migration. In addition, recombinant GPR56-NTF protein interacts with glioma cells to inhibit cellular adhesion. Inactivation of Von Hippel-Lindau (VHL) tumor-suppressor gene and hypoxia suppressed GPR56 in a renal cell carcinoma cell