Human NELL-1 Expressed in Unilateral Coronal Synostosis

Abstract

Surgical correction of unilateral coronal synostosis offers a unique opportunity to examine the molecular differences between an abnormal and a normal cranial suture. We isolated and identified a cDNA fragment whose expression was up-regulated in the premature fusing and fused coronal sutures, as compared with normal coronal sutures. The nucleotide sequence of the full-length cDNA of this gene, human NELL-1, has ∼61% homology with the chicken Nel gene. Both chicken Nel and human NELL-1 are comprised of six epidermal growth factor-like repeats. The human NELL-1 messages were localized primarily in the mesenchymal cells and osteoblasts at the osteogenic front, along the parasutural bone margins, and within the condensing mesenchymal cells of newly formed bone in sites of premature sutural fusion. Human multiorgan tissue mRNA blot showed that NELL-1 was specifically expressed in fetal brain but not in fetal kidney, liver, or lung. We also showed that Nell-1 was expressed in rat calvarial osteoprogenitor cells and was largely absent in rat tibiae and fibroblast cell cultures. In conclusion, our data suggest that the NELL-1 gene is preferentially expressed in cranial intramembranous bone and neural tissue (both of neural crest cell origin) and is up-regulated during unilateral premature closure of the coronal suture. The precise role of this gene is unknown. (J Bone Miner Res 1999;14:80-89)

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

“…6 We have previously identified exencephaly-like characteristics in Nell-1 transgenic embryos. 22,28 Our previous studies have demonstrated the role of NELL-1 in human and murine CS, 22,23,28 while the current studies were performed to further investigate the effects of Nell-1 overexpression on mouse embryonic development and the corresponding molecular mechanism.…”

“…The NELL-1 gene is preferentially expressed in neural crest derived tissues including intramembranous cranial bone and neural tissue. 23 Furthermore, our Nell-1 transgenic mouse model demonstrates craniosynostosis phenotypes of varied degrees and increased apoptosis in osteoblasts. 28 Also, AdNell-1 transduced MC3T3-E1 osteoblasts undergoing apoptosis demonstrate increased Fas expression.…”

“…19 Furthermore, in vitro and in vivo studies have demonstrated that signaling through the CD95/ Fas pathway resulted in increases apoptosis in human and murine osteoblasts. [20][21][22] We previously reported the isolation and identification of a novel gene, NELL-1, in human unilateral coronal craniosynostosis (CS) 23 (concurrently identified by Watanabe et al 24 ). NELL-1 is a secretory protein containing 810 amino acids.…”

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

“…NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, 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.…”

“…8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we demonstrated that osteoinductive effects of NELL-1 are partially mediated through binding to the intracellular molecule apoptosis related protein 3 and integrin-b 1 . 10 In translational models of bone repair, exogenous NELL-1 induces potent osseous healing of critical-sized rat calvarial defects, 11 repair of rat femoral segmental defects (FSDs), 12 as well as successful spinal fusion in rats 13,14 and sheep.…”