Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development

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 Laboratory Investigation (2006) 86, 633-644.

Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma

“…Overexpression of NELL1 increased osteoblast differentiation and reduced cell proliferation in transgenic mice, while downregulation of NELL1 using in vitro approaches demonstrated inhibited osteoblast differentiation and suggested that decreased levels of NELL1 protein lead to promoted cell proliferation at the suture line (Zhang et al, 2002). It has also been reported that overexpression of NELL1 promotes apoptosis in osteoblasts both in vitro and in vivo (Zhang et al, 2003), and that this apoptotic activity may be associated with the Fas signaling pathway (Zhang et al, 2006). In NELL1 6R mutant mice, loss of NELL1 expression was associated with reduced expression of genes encoding tumor necrosis factor receptor superfamily member 11b and extracellular matrix proteins (Desai et al, 2006), which have also been implicated in human carcinogenesis (Ingber, 2002;Rowinsky, 2005).…”

NEL-Like Molecule-1 (Nell1) Is Regulated by Bone Morphogenetic Protein 9 (BMP9) and Potentiates BMP9-Induced Osteogenic Differentiation at the Expense of Adipogenesis in Mesenchymal Stem Cells

“…Conversely, transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes [56]. Accordingly, several recent studies indicate that Nell1 exerts osteoinductive activity [55,57].…”

“…Nell1 is a large secretory glycoprotein, and was originally identified in craniosynostosis patients as being specifically upregulated within prematurely fusing sutures [53]. Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones [54,55]. Conversely, transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes [56].…”

Nfatc2 is a primary response gene of nell-1 regulating chondrogenesis in ATDC5 cells

“…(13) In addition, Nell-1 overexpression results in abnormal cartilage formation, (14) whereas loss of Nell-1 function results in reduced gene expression of extracellular matrix proteins critical for osteogenesis and chondrogenesis. (15) In this study we revealed roles for Nell-1 in the molecular regulation of chondrogenesis using ATDC5 cells, a murine embryonal carcinoma-derived chondroprogenitor cell line that undergoes a multistep chondrogenic differentiation process beginning with mesenchymal condensation and culminating in cartilage formation in vitro.…”