Departmental Papers (Dental)

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Journal Article

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Journal of Bone and Mineral Research





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Contactin-associated protein-like 4 (Cntnap4) is a member of the neurexin superfamily of transmembrane molecules that have critical functions in neuronal cell communication. Cntnap4 knockout mice display decreased presynaptic gamma-aminobutyric acid (GABA) and increased dopamine release that is associated with severe, highly penetrant, repetitive, and perseverative movements commonly found in human autism spectrum disorder patients. However, no known function of Cntnap4 has been revealed besides the nervous system. Meanwhile, secretory protein neural EGFL-like 1 (Nell-1) is known to exert potent osteogenic effects in multiple small and large animal models without the off-target effects commonly found with bone morphogenetic protein 2. In this study, while searching for a Nell-1-specific cell surface receptor during osteogenesis, we identified and validated a ligand/receptor-like interaction between Nell-1 and Cntnap4 by demonstrating: 1) Nell-1 and Cntnap4 colocalization on the surface of osteogenic-committed cells; 2) high-affinity interaction between Nell-1 and Cntnap4; 3) abrogation of Nell-1-responsive Wnt and MAPK signaling transduction, as well as osteogenic effects, via Cntnap4 knockdown; and 4) replication of calvarial cleidocranial dysplasias-like defects observed in Nell-1-deficient mice in Wnt1-Cre-mediated Cntnap4-knockout transgenic mice. In aggregate, these findings indicate that Cntnap4 plays a critical role in Nell-1-responsive osteogenesis. Further, this is the first functional annotation for Cntnap4 in the musculoskeletal system. Intriguingly, Nell-1 and Cntnap4 also colocalize on the surface of human hippocampal interneurons, implicating Nell-1 as a potential novel ligand for Cntnap4 in the nervous system. This unexpected characterization of the ligand/receptor-like interaction between Nell-1 and Cntnap4 indicates a novel biological functional axis for Nell-1 and Cntnap4 in osteogenesis and, potentially, in neural development and function. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research


At the time of publication, author Chenshuang Li was affiliated with the School of Dentistry, University of California. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.


CONTACTIN-ASSOCIATED PROTEIN-LIKE 4 (CNTNAP4), LIGAND/RECEPTOR-LIKE INTERACTION, NELL-1/CNTNAP4 AXIS, NEURAL EGFL-LIKE 1 (NELL-1), OSTEOGENESIS, Amino Acid Sequence, Animals, Animals, Newborn, Bacteriophage T7, Bone Marrow, Calcium-Binding Proteins, Cell Line, Cell Lineage, Cell Membrane, Gene Deletion, Glycoproteins, Humans, Integrases, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Nerve Tissue Proteins, Osteogenesis, Protein Binding, Protein Domains, Signal Transduction, Skull, alkaline phosphatase, bacteriophage DNA, bone morphogenetic protein 2, bone sialoprotein, cell surface receptor, collagen type 1 alpha 1, collagen type 1 alpha 2, contactin, contactin associated protein like 4, membrane receptor, mitogen activated protein kinase, neural egfl like 1, neurexin, osteocalcin, osteopontin, unclassified drug, Wnt1 protein, calcium binding protein, Cntnap4 protein, mouse, cre recombinase, glycoprotein, integrase, membrane protein, Nell1 protein, mouse, nerve protein, protein binding, amino acid sequence, animal cell, animal experiment, animal model, animal tissue, Article, binding affinity, biopanning, bone development, bone mineralization, calvaria, cell differentiation, cell membrane, chondrocyte, cleidocranial dysplasia, controlled study, Enterobacteria phage T7, enzyme phosphorylation, gene expression profiling, gene knockdown, hematopoietic stem cell, human, human cell, interneuron, ligand binding, MAPK signaling, MC3T3-E1 cell line, micro-computed tomography, mouse, nonhuman, ossification, osteoblast, PDZ domain, phage display, protein family, protein function, protein localization, protein protein interaction, receptor binding, RNA interference, upregulation, Wnt signaling, animal, biological model, bone marrow, C57BL mouse, cell line, cell lineage, chemistry, gene deletion, knockout mouse, metabolism, newborn, protein domain, signal transduction, skull

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Date Posted: 10 February 2023

This document has been peer reviewed.