Tspan5, a member of the tetraspanin family, has diverse functions. It can organize specific membrane domains. Tspan5 is involved in multiple biological processes and associated with various pathways, such as Notch signaling, and is of great biological importance [1,2,8]. Genetic models like KO/CKO mouse models are valuable for studying its functions.

In placental trophoblast cells, Tspan5 promotes the epithelial-mesenchymal transition (EMT) process by activating Notch signaling, regulating trophoblast cell syncytialization, which is crucial for placental development [1]. In hepatocellular carcinoma (HCC), Tspan5 promotes EMT and tumor metastasis by increasing ADAM10 enzymatic maturation and activating Notch signaling [2].

In neurons, Tspan5 knockdown leads to a decrease in dendritic spine number due to spine maturation defects as it interacts with neuroligin-1 for its surface clustering [3]. In human induced pluripotent stem cell-derived neurons and astrocytes, ethanol or acamprosate treatment downregulates Tspan5 expression, influencing serotonin and kynurenine concentrations [4].

In rat hippocampal neurons, Tspan5 promotes AMPA receptor exocytosis by interacting with the AP4 complex [5].

In gastric cancer, Tspan5 acts as a tumor suppressor, inhibiting cell proliferation and colony formation [6]. In HCC, depletion of Tspan5 induces oncogene-induced senescence via the p16INK4a/pRb pathways [7].

In conclusion, Tspan5 plays essential roles in multiple biological processes, including cell fusion in trophoblasts, synaptic development in neurons, and tumor-related processes in cancers. Studies using KO/CKO mouse models or other loss-of-function experiments have significantly contributed to understanding its functions in these disease-related areas.