title: Calvarial cleidocraniodysplasia-like defects with ENU-induced Nell-1 deficiency.
abstract: 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.
authors.affiliation: 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, Los Angeles, California 90095, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
authors.forename: Dharmini
authors.initials: D
authors.lastname: Pathmanathan
authors.forename: Theodore
authors.initials: T
authors.lastname: Ko
authors.forename: Weiwei
authors.initials: W
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Haofu
authors.initials: H
authors.lastname: Lee
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Siu
authors.forename: Jia
authors.initials: J
authors.lastname: Shen
authors.forename: Cymbeline T
authors.initials: CT
authors.lastname: Culiat
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
mesh_terms: D000469:Alkaline Phosphatase / Q000032:analysis; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density / Q000235:genetics; D001846:Bone Development / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002574:Cervical Vertebrae / Q000473:pathology; D019902:Chondrocytes / Q000473:pathology; D020219:Chondrogenesis / Q000502:physiology; D002973:Cleidocranial Dysplasia / Q000209:etiology*; D018388:Codon, Terminator / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000032:analysis; D003393:Cranial Sutures / Q000473:pathology; D005624:Frontal Bone / Q000473:pathology; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics; D008334:Mandible / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009295:Nasal Bone / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology; D015675:Osteocalcin / Q000032:analysis; D010012:Osteogenesis / Q000502:physiology; D010294:Parietal Bone / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000032:analysis; D012697:Serine Endopeptidases / Q000032:analysis; D012886:Skull / Q000254:growth & development / Q000473:pathology*
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; D018388:Codon, Terminator; D050659:Core Binding Factor Alpha 1 Subunit; D006023:Glycoproteins; C513122:Nell1 protein, mouse; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D015675:Osteocalcin; D000469:Alkaline Phosphatase; C114665:Prss22 protein, mouse; D012697:Serine Endopeptidases