ABSTRACT
Neuronal leucine-rich repeat proteins (NLRRs) are type I transmembrane proteins and expressed in neuronal tissues, but their function remains unknown. Here, we describe the identification and characterization of a new member of the NLRR family, NLRR4, and its potential role in long-lasting memory. We generated NLRR4-deficient (NLRR4(-/-)) mice and found that they showed impaired memory retention. In hippocampus-dependent learning tasks, NLRR4(-/-) mice were able to learn and maintain the memories for one day but unable to retain the memories for four days after learning. In contrast, in a hippocampus-independent task, NLRR4(-/-) mice were able to retain the memory normally for at least seven days. These results suggest that NLRR4 plays a key role in hippocampus-dependent long-lasting memory.
Subject(s)
Hippocampus/physiology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Memory/physiology , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Amino Acid Sequence , Animals , Brain/metabolism , Brain/physiopathology , Cloning, Molecular , Cues , Fear/physiology , Gene Deletion , Hippocampus/metabolism , Hippocampus/physiopathology , Long-Term Potentiation/physiology , Maze Learning/physiology , Membrane Proteins/chemistry , Membrane Proteins/deficiency , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Molecular Sequence Data , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/deficiency , RNA, Messenger/genetics , RNA, Messenger/metabolism , Synaptic Transmission/physiologyABSTRACT
Mesothelin is a glycosylphosphatidylinositol-linked cell surface molecule expressed in the mesothelial lining of the body cavities and in many tumor cells. Based on the finding that a soluble form of mesothelin specifically binds to ovarian carcinoma cell line OVCAR-3, we isolated cDNAs encoding a mesothelin-binding protein by expression cloning. The polypeptides encoded by the two cloned cDNA fragments matched to portions of CA125, an ovarian cancer antigen and a giant mucin-like glycoprotein present at the surface of tumor cells. By flow cytometric analysis and immunoprecipitation, we demonstrate that CA125 binds to mesothelin in a specific manner. Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin. Finally, we show that CA125 and mesothelin are co-expressed in advanced grade ovarian adenocarcinoma. Taken together, our data indicate that mesothelin is a novel CA125-binding protein and that CA125 might contribute to the metastasis of ovarian cancer to the peritoneum by initiating cell attachment to the mesothelial epithelium via binding to mesothelin.