Overexpression of Nell-1, a craniosynostosis-associated gene, induces apoptosis in osteoblasts during craniofacial development.
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.
Zhang
Xinli
X
Dental and Craniofacial Research Institute, University of California at Los Angeles, Los Angeles, California, USA.
Carpenter
Dale
D
Bokui
Nobuyuki
N
Soo
Chia
C
Miao
Steve
S
Truong
Thien
T
Wu
Benjamin
B
Chen
Ingrid
I
Vastardis
Heleni
H
Tanizawa
Katsuyuki
K
Kuroda
Shun'ichi
S
Ting
Kang
K
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
D002135:Calcium-Binding Proteins; D017931:DNA Primers; C104144:NELL1 protein, human; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins