Nell-1, first identified by its overexpression in synostotic cranial sutures, is a novel osteoinductive growth and differentiation factor. To further define Nell-1’s role in craniofacial patterning, we characterized defects of the ENU-induced Nell-1–deficient (END) mice, focusing on both intramembranous and endochondral cranial bones. Results showed that calvarial bones of neonatal END mice were reduced in thickness and density, with a phenotype resembling calvarial cleidocraniodysplasia. In addition, a global reduction in osteoblast markers was observed, including reductions in Runx2, alkaline phosphatase, and osteocalcin. Remarkably, detailed analysis of endochondral bones showed dysplasia as well. The chondrocranium in the END mouse showed enrichment for early, proliferating Sox9+ chondrocytes, whereas in contrast markers of chondrocytes maturation were reduced. These data suggest that Nell-1 is an important growth factor for regulation of osteochondral differentiation, by regulating both Runx2 and Sox9 expression within the calvarium. In summary, Nell-1 is required for normal craniofacial membranous and endochondral skeletal development.
From the *Dental and Craniofacial Research Institute, †Section of Orthodontics, School of Dentistry, ‡UCLA and Orthopaedic Hospital Department of Orthopedic Surgery and the Orthopaedic Hospital Research Center, and §Department of Bioengineering, School of Engineering, University of California, Los Angeles, California; and ∥Oak Ridge National Laboratory, Oak Ridge, Tennessee.
Received March 2, 2011.
Accepted for publication March 21, 2011.
Address correspondence and reprint requests to Kang Ting, DMD, DMedSci, University of California, Los Angeles, Le Conte Ave, CHS 30-117, Los Angeles, CA 90095; E-mail: firstname.lastname@example.org
This work was supported by the NIH/NIDCR (grants R21 DE0177711 and RO1 DE01607), UC Discovery Grant 07-10677, and the Thomas R. Bales Endowed Chair.
Drs. Zhang, Ting, and Soo are inventors of Nell-1–related patents filed from UCLA. Dr. Culiat is an inventor of Nell-1–related patents filed from ORNL. Drs. Ting, Soo, and Zhang are cofounders of Bone Biologics Inc, which licensed Nell-1–related patent applications from UCLA. Dr. Culiat is a founder of NellOne Therapeutics, Inc, which licensed Nell-1–related patent applications from ORNL.