Alternative titles; symbols
HGNC Approved Gene Symbol: NELL1
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:20,669,551-21,575,686 (from NCBI)
NELL1 is a secreted protein that stimulates osteoblast proliferation and differentiation and induces bone formation and regeneration. It is also a positive regulator of tooth development and odontoblast differentiation (Tian et al., 2019).
Proteins containing epidermal growth factor (EGF)-like repeats are often involved in growth regulation and differentiation. During a random sequencing project, Watanabe et al. (1996) identified 2 novel genes encoding proteins with 6 EGF-like repeats. These novel genes resembled the chicken gene 'nel' and thus were named nel-like 1 (NELL1) and nel-like 2 (NELL2; 602320). The NELL1 open reading frame encodes an 810-amino acid polypeptide. Both NELL1 and NELL2 include a secretory signal sequence but no transmembrane domains. The NELL1 amino acid sequence exhibits 50% identity to that of chicken nel. Using Northern blot analysis, Watanabe et al. (1996) showed that NELL1 was expressed weakly as a 3.5-kb transcript in human adult and fetal brain and kidney tissues.
Desai et al. (2006) first detected mouse Nell1 expression at embryonic day 10, after which expression steadily increased in the head region and decreased in the body. In adult tissues, Nell1 expression was observed primarily in brain.
By Western blot and RT-PCR analyses, Tian et al. (2019) showed that NELL1 and APR3 (ATRAID; 619682) had similar spatiotemporal expression patterns in human dental pulp cells during proliferation and differentiation. Immunofluorescence analysis revealed that NELL1 and APR3 were primarily present in cytosol of human dental pulp cells.
Watanabe et al. (1996) used fluorescence in situ hybridization to map the NELL1 gene to human chromosome 11p15.2-p15.1.
Desai et al. (2006) stated that the mouse Nell1 gene maps to a region of chromosome 7 that shares homology of synteny with human chromosome 11p15.
By immunoprecipitation analysis, Tian et al. (2019) showed that APR3 and NELL1 interacted in human dental pulp cells. APR3 functioned as cofactor of NELL1 in enhancing differentiation and mineralization of human dental pulp cells. APR3 inhibited the proliferation of human dental pulp cells by reducing expression of cyclin D1 (CCND1; 168461), driving cells toward differentiation and terminal mineralization. NELL1 could reciprocally interact with APR3 to enhance differentiation and mineralization of cells.
Using an N-ethyl-N-nitrosourea mutagenesis screen, Desai et al. (2006) identified a recessive mutation in the mouse Nell1 gene that they called l7R6(6R) or Nell1(6R). The Nell1(6R) point mutation resulted in a cys502-to-ter (C502X) substitution that led to mRNA instability. Homozygosity for Nell1(6R) caused neonatal lethality with enlarged skull and pronounced body curling. Nell1(6R) heterozygotes grew and developed normally. Death in Nell1(6R) neonates appeared to be due to birth trauma, and fetuses rescued by caesarean section succumbed due to inability to breathe. Skeletal analysis revealed compression of intervertebral spaces and alteration in spinal curvature with anomalies in the shape and volume of the rib cage. Cranial abnormalities included enlargement and thinning of the parietal, frontal, and interparietal bones, and nasal bones were enlarged without thinning. Real-time quantitative RT-PCR revealed that the Nell1(6R) mutation caused reduced expression of numerous genes encoding extracellular matrix, cell adhesion, and cell communication proteins required for chondrogenesis and osteogenesis. At least 8 of the affected genes are necessary for development of and/or are specific constituents of the intervertebral disc matrix, and mutations in 2 of the affected genes, Col5a1 (120130) and Tnxb (600985), cause Ehlers-Danlos syndrome type I (130000) and type III (130020), respectively. Desai et al. (2006) concluded that NELL1 plays a key role in both intramembranous and endochondral ossification during early development.
Desai, J., Shannon, M. E., Johnson, M. D., Ruff, D. W., Hughes, L. A., Kerley, M. K., Carpenter, D. A., Johnson, D. K., Rinchik, E. M., Culiat, C. T. Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Hum. Molec. Genet. 15: 1329-1341, 2006. [PubMed: 16537572] [Full Text: https://doi.org/10.1093/hmg/ddl053]
Tian, X., Wang, Q., Wu, J., Han, Q., Shen, L., Wei, C., Song, H., Li, M., Fang, Y., Wang, X., Sun, Q. Interaction of Nel-like molecule 1 with apoptosis related protein 3 with its influence on human dental pulp cells proliferation and differentiation into odontoblasts. Biochem. Biophys. Res. Commun. 518: 246-252, 2019. [PubMed: 31416616] [Full Text: https://doi.org/10.1016/j.bbrc.2019.08.042]
Watanabe, T. K., Katagiri, T., Suzuki, M., Shimizu, F., Fujiwara, T., Kanemoto, N., Nakamura, Y., Hirai, Y., Maekawa, H., Takahashi, E. Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 38: 273-276, 1996. [PubMed: 8975702] [Full Text: https://doi.org/10.1006/geno.1996.0628]