ADAMTSL3 (ADAMTS-like 3) is a secreted extracellular matrix protein with diverse roles across multiple physiological systems. Structurally, it resembles ADAMTS proteases and contains thrombospondin-type domains 1. ADAMTSL3 mediates synaptic organization in the hippocampus through DCC (deleted in colorectal cancer) receptor signaling, selectively promoting GABAergic synapse function and activity-dependent plasticity via DCC phosphorylation and Src kinase activation 2. Genetically, ADAMTSL3 variants associate with lean body mass and appendicular muscle mass in large meta-analyses 3, and specific polymorphisms correlate with body measurement traits in cattle 4. The gene has broader tissue expression including epithelial cells, vascular endothelium, neurons, and cardiac myocytes 1. Disease relevance spans multiple conditions: schizophrenia-associated variants implicate altered DCC signaling and GABAergic function 52, reduced ADAMTSL3 expression occurs in colorectal cancer and correlates with poor survival outcomes 16, and decreased expression appears in periodontitis gingival tissues with hypermetylation 7. ADAMTSL3 may contribute to human cognitive evolution as a von Economo neuron marker gene 8. These findings suggest ADAMTSL3 functions as a multifaceted extracellular regulator critical for skeletal development, synaptic homeostasis, and tumor suppression.