title: Craniosynostosis in transgenic mice overexpressing Nell-1.
abstract: 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.
authors.affiliation: Dental and Craniofacial Research Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Xinli
authors.initials: X
authors.lastname: Zhang
authors.forename: Shun'ichi
authors.initials: S
authors.lastname: Kuroda
authors.forename: Dale
authors.initials: D
authors.lastname: Carpenter
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishimura
authors.forename: Chia
authors.initials: C
authors.lastname: Soo
authors.forename: Rex
authors.initials: R
authors.lastname: Moats
authors.forename: Keisuke
authors.initials: K
authors.lastname: Iida
authors.forename: Eric
authors.initials: E
authors.lastname: Wisner
authors.forename: Fei-Ya
authors.initials: FY
authors.lastname: Hu
authors.forename: Steve
authors.initials: S
authors.lastname: Miao
authors.forename: Steve
authors.initials: S
authors.lastname: Beanes
authors.forename: Catherine
authors.initials: C
authors.lastname: Dang
authors.forename: Heleni
authors.initials: H
authors.lastname: Vastardis
authors.forename: Michael
authors.initials: M
authors.lastname: Longaker
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tanizawa
authors.forename: Norihiro
authors.initials: N
authors.lastname: Kanayama
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.forename: Kang
authors.initials: K
authors.lastname: Ting
mesh_terms: 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
chemical_list: D015415:Biomarkers; D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins