Zhang Xinli, Cowan Catherine M, Jiang Xinquan, Soo Chia, Miao Steve, Carpenter Dale, Wu Benjamin, Kuroda Shun'ichi, Ting Kang
Dental and Craniofacial Research Institute, University of California, Los Angeles, CA 90095, USA.
Lab Invest. 2006 Jul;86(7):633-44. doi: 10.1038/labinvest.3700430. Epub 2006 May 1.
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.
我们之前报道过NELL-1是一种在颅缝早闭（CS）患者的颅骨缝线过早闭合期间过度表达的新型分子。Nell-1的过度表达在新生转基因小鼠中也会导致缝线过早闭合/颅缝早闭。在细胞水平上，Nell-1水平的升高会诱导成骨细胞分化和凋亡。在本报告中，对过表达Nell-1的小鼠在胚胎发育期间以及出生后不久进行了检查，以进一步分析包括神经管缺陷（NTDs）在内的颅面缺陷。结果表明，Nell-1的过表达可在小鼠胚胎相对较晚的妊娠阶段（E15.5）通过颅盖成骨细胞和神经细胞的大量凋亡诱导无脑畸形。诱导的凋亡与Fas和Fas-L产生的增加有关。此外，具有CS表型的转基因E15.5和新生转基因小鼠表现出软骨颅的变形，伴有软骨细胞过早肥大和凋亡增加。这些发现也在用AdNell-1转导的原代软骨细胞进行的体外实验中得到了验证。总之，Nell-1的过表达可在胚胎发育期间诱导与神经管缺陷相关的颅面异常，并且可能涉及与Fas/Fas-L信号通路相关的大量凋亡机制。NELL-1：用于描述人类基因时；NELL-1：用于描述人类蛋白质时；Nell-1：用于描述啮齿动物基因时；Nell-1：用于描述啮齿动物蛋白质时。
