Biochemical Characterization and Expression Analysis of Neural Thrombospondin-1-like Proteins NELL1 and NELL2

Kuroda, Shinya; Oyasu, Miho; Kawakami, Masakatsu; Kanayama, Naoyuki; Tanizawa, Katsuyuki; Saito, Naoaki; Abe, Teruo; Matsuhashi, Sachiko; Ting, Kang

doi:10.1006/bbrc.1999.1638

Cited by 125 publications

(156 citation statements)

References 25 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…Paraffin embedded sections were incubated with anti-Nell-1 antibody, 26 anti-Fas antigen, or anti-Fasligand antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at a 1:100 dilution. ABC complex (Vector Laboratories, Burlingame, CA, USA) was applied on the sections following the incubation with biotinylated secondary antibody (Dako Corporation, Carpinteria, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

See 1 more Smart Citation

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

Zhang

Cowan

Jiang

et al. 2006

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Immunohistochemistrymentioning

confidence: 99%

“…NELL-1 is a secretory protein containing 810 amino acids. 25,26 NELL-1 encodes a secretory signal peptide sequence, an NH 2 -terminal thrombospondin (TSP)-like module, five von Willebrand factor C domains, and six EGFlike domains. 27 NELL-1 expression is upregulated in fused or prematurely fusing coronal sutures as compared to wild-type coronal sutures.…”

mentioning

confidence: 99%

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

Zhang

Cowan

Jiang

et al. 2006

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…NELL1 protein consists of about 810 amino acid residues (aa) and harbors an about 20-aa signal peptide, an about 128-aa laminin G domain [previously known as an N-terminal thrombospondin (TSP)-like module], five von Willebrand factor C domains, and six EGF-like domains including three Ca 2+ -binding types [5], as shown in Fig. 1.…”

Section: Introductionmentioning

confidence: 99%

Involvement of MAPK signaling molecules and Runx2 in the NELL1‐induced osteoblastic differentiation

Bokui

Otani²,

Igarashi³

et al. 2007

FEBS Letters

Self Cite

View full text Add to dashboard Cite

NELL1 is an extracellular protein inducing osteogenic differentiation and bone formation of osteoblastic cells. To elucidate the intracellular signaling cascade evoked by NELL1, we have shown that NELL1 protein transiently activates the MAPK signaling cascade, induces the phosphorylation of Runx2, and promotes the rapid intracellular accumulation of Tyr-phosphorylated proteins. Unlike BMP2, NELL1 protein does not activate the Smad signaling cascade. These findings suggest that upon binding to a specific receptor NELL1 transduces an osteogenic signal through activation of certain Tyrkinases associated with the Ras-MAPK cascade, and finally leads to the osteogenic differentiation.

show abstract

“…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.…”

mentioning

confidence: 99%

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

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. 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. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

show abstract

Biochemical Characterization and Expression Analysis of Neural Thrombospondin-1-like Proteins NELL1 and NELL2

Cited by 125 publications

References 25 publications

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

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

Involvement of MAPK signaling molecules and Runx2 in the NELL1‐induced osteoblastic differentiation

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

Contact Info

Product

Resources

About