Craniosynostosis in transgenic mice overexpressing Nell-1

Xinli Zhang, Shun'ichi Kuroda, Dale Carpenter, Ichiro Nishimura, Chia Soo, Rex Moats, Keisuke Iida, Erik R Wisner, Fei Ya Hu, Steve Miao, Steve Beanes, Catherine Dang, Heleni Vastardis, Michael Longaker, Katsuyuki Tanizawa, Norihiro Kanayama, Naoaki Saito, Kang Ting

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119 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)861-870
Number of pages10
JournalJournal of Clinical Investigation
Volume110
Issue number6
DOIs
StatePublished - Sep 2002

ASJC Scopus subject areas

  • Medicine(all)

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    Zhang, X., Kuroda, S., Carpenter, D., Nishimura, I., Soo, C., Moats, R., Iida, K., Wisner, E. R., Hu, F. Y., Miao, S., Beanes, S., Dang, C., Vastardis, H., Longaker, M., Tanizawa, K., Kanayama, N., Saito, N., & Ting, K. (2002). Craniosynostosis in transgenic mice overexpressing Nell-1. Journal of Clinical Investigation, 110(6), 861-870. https://doi.org/10.1172/JCI200215375