1. ¹Dental and Craniofacial Research Institute, University of California, Los Angeles, CA, USA
2. ²Department of Bioengineering, University of California, Los Angeles, CA, USA
3. ³Oral Bioengineering Laboratory, Shanghai Research Institute of Stomatology, Shanghai Second Medical University, Shanghai, China
4. ⁴Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Southern California, Los Angeles, CA, USA
5. ⁵Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
6. ⁶Department of Ophthalmology, University of California, Irvine, CA, USA
7. ⁷Research Center, Kobe University, Kobe, Japan
8. ⁸Department of Structural Molecular Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan

Correspondence: Dr K Ting, DMD, DMEDSC, Dental and Craniofacial Research Institute, University of California, 10833 Le Conte Avenue, CHS 30-117, Los Angeles, CA 90095, USA. E-mail: kting@ucla.edu

^*Co-senior authors.

Received 3 November 2005; Revised 16 March 2006; Accepted 21 March 2006; Published online 1 May 2006.

Abstract

We previously reported NELL-1 as a novel molecule overexpressed during premature cranial suture closure in patients with craniosynostosis (CS). Nell-1 overexpression also results in premature suture closure/craniosynostosis in newborn transgenic mice. On a cellular level, increased levels of Nell-1 induce osteoblast differentiation and apoptosis. In this report, mice over-expressing Nell-1 were examined during embryonic development as well as shortly after birth for further analysis of craniofacial defects including neural tube defects (NTDs). The results demonstrated that overexpression of Nell-1 could induce acrania at relatively late gestation stage (E15.5) in mouse embryos, through massive apoptosis in calvarial osteoblasts and neural cells. The induced apoptosis was associated with an increase in Fas and Fas-L production. In addition, transgenic E15.5 and newborn transgenic mice with the CS phenotype displayed distortion of the chondrocranium associated with premature hypertrophy and increased apoptosis of chondrocytes. These findings were also verified in vitro with primary chondrocytes transduced with AdNell-1. In conclusion, Nell-1 overexpression can induce craniofacial anomalies associated with neural tube defects during embryonic development and may involve mechanisms of massive apoptosis associated with the Fas/Fas-L signaling pathway. NELL-1: used when describing the human gene; NELL-1: used when describing the human protein; Nell-1: used when describing the rodent gene; Nell-1: used when describing the rodent protein