title: Overexpression of Nell-1, a craniosynostosis-associated gene, induces apoptosis in osteoblasts during craniofacial development.
abstract: We studied the cellular function of Nell-1, a craniosynostosis-related gene, in craniofacial development. Nell-1 modulates calvarial osteoblast differentiation and apoptosis pathways. Nell-1 overexpression disrupts these pathways resulting in craniofacial anomalies such as premature suture closure.
  
  
  BACKGROUND
  Craniosynostosis (CS), one of the most common congenital craniofacial deformities, is the premature closure of cranial sutures. Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with CS. Nell-1 overexpression induced calvarial overgrowth and resulted in premature suture closure in a rodent model. On a cellular level, Nell-1 is suggested to promote osteoblast differentiation.
  
  
  METHODS
  Different levels of Nell-1 were introduced into osteoblastic cells by viral infection and recombinant protein. Apoptosis and gene expression assays were performed. Mice overexpressing Nell-1 were examined for apoptosis.
  
  
  RESULTS
  In this report, we further showed that overexpression of Nell-1 induced apoptosis along with modulation of apoptosis-related genes. The induction of apoptosis by Nell-1 was observed only in osteoblastic cells and not in NIH3T3 or primary fibroblasts. The CS mouse model overexpressing Nell-1 showed increased levels of apoptosis in the calvaria.
  
  
  CONCLUSIONS
  We show that Nell-1 expression modulates calvarial osteoblast differentiation and apoptosis pathways. Nell-1 overexpression disrupts these pathways resulting in craniofacial anomalies such as premature suture closure.
authors.affiliation: Dental and Craniofacial Research Institute, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Dale
authors.initials: D
authors.lastname: Carpenter
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Bokui
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
authors.forename: Steve
authors.initials: S
authors.lastname: Miao
authors.forename: Thien
authors.initials: T
authors.lastname: Truong
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wu
authors.forename: Ingrid
authors.initials: I
authors.lastname: Chen
authors.forename: Heleni
authors.initials: H
authors.lastname: Vastardis
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanizawa
authors.forename: Shun'ichi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D016923:Cell Death; D019465:Craniofacial Abnormalities / Q000235:genetics*; D003398:Craniosynostoses / Q000235:genetics*; D017931:DNA Primers; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology*; D051381:Rats
chemical_list: D002135:Calcium-Binding Proteins; D017931:DNA Primers; C104144:NELL1 protein, human; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins