UCLA

Secretory protein neural EGFL like 1 (Nell-1) has been shown to exert potent osteogenic effects in multiple small and large animal models. Here, we identified and validated contactin-associated protein-like 4 (Cntnap4) as the first Nell-1 specific cell surface receptor. Cntnap4, a transmembrane neurexin superfamily protein member, has critical functions in neurodevelopment but no known function in osteogenesis. In the present study, we demonstrate that: 1) Nell-1 and Cntnap4 co-localize on the surface of osteogenic-committed cells, 2) Nell-1 and Cntnap4 exhibit high-affinity interactions, 3) Cntnap4 knockdown reduces Nell-1-responsive osteogenesis, and 4) Cntnap4 mediates Nell-1-activated MAPK and Wnt signaling in osteogenic-committed cells. Taken together, these findings and recent literature further the notion of potential neuroskeletal interplay. This unanticipated discovery connecting Cntnap4 to Nell-1 during osteogenesis provides a foundational framework for further exploration of a novel functional axis as it relates to skeletal and potential neuronal function.