Craniosynostosis in transgenic mice overexpressing Nell-1.
Previously, we reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS), one of the most common congenital craniofacial deformities. Here we describe the creation and analysis of transgenic mice overexpressing Nell-1. Nell-1 transgenic animals exhibited CS-like phenotypes that ranged from simple to compound synostoses. Histologically, the osteogenic fronts of abnormally closing/closed sutures in these animals revealed calvarial overgrowth and overlap along with increased osteoblast differentiation and reduced cell proliferation. Furthermore, anomalies were restricted to calvarial bone, despite generalized, non-tissue-specific overexpression of Nell-1. In vitro, Nell-1 overexpression accelerated calvarial osteoblast differentiation and mineralization under normal culture conditions. Moreover, Nell-1 overexpression in osteoblasts was sufficient to promote alkaline phosphatase expression and micronodule formation. Conversely, downregulation of Nell-1 inhibited osteoblast differentiation in vitro. In summary, Nell-1 overexpression induced calvarial overgrowth resulting in premature suture closure in a rodent model. Nell-1, therefore, has a novel role in CS development, perhaps as part of a complex chain of events resulting in premature suture closure. On a cellular level, Nell-1 expression may modulate and be both sufficient and required for osteoblast differentiation.
Zhang
Xinli
X
Dental and Craniofacial Research Institute, University of California, Los Angeles, California 90095, USA.
Kuroda
Shun'ichi
S
Carpenter
Dale
D
Nishimura
Ichiro
I
Soo
Chia
C
Moats
Rex
R
Iida
Keisuke
K
Wisner
Eric
E
Hu
Fei-Ya
FY
Miao
Steve
S
Beanes
Steve
S
Dang
Catherine
C
Vastardis
Heleni
H
Longaker
Michael
M
Tanizawa
Katsuyuki
K
Kanayama
Norihiro
N
Saito
Naoaki
N
Ting
Kang
K
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000473:pathology; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000502:physiology; D051381:Rats; D012886:Skull / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
D015415:Biomarkers; D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins