Alternative titles; symbols
HGNC Approved Gene Symbol: NELL2
Cytogenetic location: 12q12 Genomic coordinates (GRCh38): 12:44,508,275-44,921,848 (from NCBI)
During development, NELL2 appears to function as a repulsive guidance cue for commissural axons, helping to steer them across the spinal cord midline (Jaworski et al., 2015). NELL2 is also secreted by testicular germ cells and regulates male fertility (Kiyozumi et al., 2020).
Proteins containing epidermal growth factor (EGF; 131530)-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; 602319) and nel-like 2 (NELL2). Watanabe et al. (1996) found that the NELL2 open reading frame encodes an 816-amino acid polypeptide. The amino acid sequence of NELL2 showed 80% identity to that of chicken 'nel,' and Watanabe et al. (1996) stated that NELL2 may be the actual interspecies homolog of the 'nel' gene. Using Northern blot analysis, Watanabe et al. (1996) showed that NELL2 was strongly expressed as a 3.6-kb transcript in human adult and fetal brain tissues.
Jaworski et al. (2015) stated that mouse Nell2 is a secreted glycoprotein containing a laminin (see 150320) globular-like domain, 6 EGF-like domains, and 5 von Willebrand factor (see 613160) type C domains. In situ hybridization of embryonic day-9.5 mouse spinal cord detected Nell2 expression predominately in the presumptive motor column of the ventral horn. At embryonic day 10.5, it was also expressed in dorsal root ganglia, dorsal mantle layer of the spinal cord, and a triangular population of cells close to the ventricle.
Watanabe et al. (1996) used fluorescence in situ hybridization to map the NELL2 gene to human chromosome 12q13.11-q13.12.
Gross (2016) mapped the NELL2 gene to chromosome 12q12 based on an alignment of the NELL2 sequence (GenBank BC020544) with the genomic sequence (GRCh38).
Jaworski et al. (2015) found that the isolated ectodomain of mouse Robo3 (608630) fused to the IgG (see 147100) Fc fragment (Robo3-ECD-Fc) bound Nell2-Fc. Robo3-ECD-Fc also bound GFP-tagged Nell2 expressed in HEK293T cells. A Nell2-alkaline phosphatase (see 171760) chimera bound the Robo3 isoforms Robo3.1 and Robo3.2. Deletion analysis revealed that the EGF-like domains of Nell2 bound the fibronectin (see 135600) III domains of Robo3. Explants of commissural axons of embryonic mouse dorsal spinal cord, which express Robo3.1, grew away from COS-7 cells expressing Nell2, whereas explants of postcrossing commissural axons, which express Robo3.2, did not. Robo3- and Nell2-knockout studies in mice confirmed that Nell2 provided a repulsive guidance cue to prevent commissural axons from entering the motor column.
By examining knockout mouse models, Kiyozumi et al. (2020) found that Nell2 was secreted by testicular germ cells, bound the receptor Ros1 (165020), and regulated epididymal initial segment maturation and subsequent secretion of Ovch2 (618962). Ovch2 processed the sperm surface protein Adam3 to its mature form, a requirement for sperm fertilizing ability. The authors concluded that NELL2 is part of a lumicrine system essential for male fertility.
Kiyozumi et al. (2020) found that male Nell2 -/- mice were sterile. Ovch2 was not secreted and Adam3 was not processed into its mature form in Nell2 -/- cauda epididymal spermatozoa, leading to inability of spermatozoa to pass through the uterotubal junction and to bind to the zona pellucida.
Gross, M. B. Personal Communication. Baltimore, Md. 11/30/2016.
Jaworski, A., Tom, I., Tong, R. K., Gildea, H. K., Koch, A. W., Gonzalez, L. C., Tessier-Lavigne, M. Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2. Science 350: 961-965, 2015. [PubMed: 26586761] [Full Text: https://doi.org/10.1126/science.aad2615]
Kiyozumi, D., Noda, T., Yamaguchi, R., Tobita, T., Matsumura, T., Shimada, K., Kodani, M., Kohda, T., Fujihara, Y., Ozawa, M., Yu, Z., Miklossy, G., Bohren, K. M., Horie, M., Okabe, M., Matzuk, M. M., Ikawa, M. NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility. Science 368: 1132-1135, 2020. [PubMed: 32499443] [Full Text: https://doi.org/10.1126/science.aay5134]
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]