Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development.
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.
Zhang
Xinli
X
Dental and Craniofacial Research Institute, University of California, Los Angeles, CA 90095, USA.
Cowan
Catherine M
CM
Jiang
Xinquan
X
Soo
Chia
C
Miao
Steve
S
Carpenter
Dale
D
Wu
Benjamin
B
Kuroda
Shun'ichi
S
Ting
Kang
K
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D006023:Glycoproteins; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010006:Osteoblasts / Q000502:physiology; D011247:Pregnancy
D002135:Calcium-Binding Proteins; D006023:Glycoproteins; C513122:Nell1 protein, mouse; D009419:Nerve Tissue Proteins