Neuregulins, including NRG3, form a family of neurally expressed proteins that perform a wide range of functions in the developing nervous system (Carteron et al., 2006). For general information on the neuregulin gene family, see NRG2 (603818).

By EST database searching, Zhang et al. (1997) identified ESTs with sequence homology to NRG1 (142445) which they used to isolate human and mouse NRG3 cDNAs from fetal brain and brain cDNA libraries, respectively. The human NRG3 cDNA encodes a 720-amino acid protein that shares 93% sequence identity with mouse Nrg3. Human NRG3 contains 2 hydrophobic segments similar to those in NRG1 which function as a transmembrane domain and internal signal sequence. NRG3 also contains a unique N-terminal alanine/glycine-rich segment, an epidermal growth factor (EGF; 131530) motif, and a mucin-like serine/threonine-rich region with abundant sites for O-linked glycosylation. Using Northern blot analysis, Zhang et al. (1997) detected a 4.4-kb NRG3 transcript at high levels in many regions of the brain with the exception of corpus callosum. An additional 1.9-kb NRG3 transcript was detected at low levels in the testis. Using in situ hybridization with embryonic and adult mouse tissues, Zhang et al. (1997) detected restricted expression of Nrg3 in the developing and adult nervous system. High expression was detected in spinal cord, trigeminal, vestibular-cochlear, and spinal ganglia, and brain regions, including the deep cerebellar nuclei, vestibular nuclei, cerebral cortex, piriform cortex, anterior olfactory nucleus, medial habenula, hippocampus, hypothalamus, and thalamus.

Carteron et al. (2006) identified an NRG3 variant expressed specifically in human fetal brain with a predicted molecular mass of 56 kD. The N terminus of the variant contained 54 amino acids compared to the 275 amino acids of the transcript described by Zhang et al. (1997). Immunoblot analysis of transfected COS-7 cells detected a 50-kD transcript and a larger 70-kD transcript, only after proteasome inhibition. The N terminus contains a signal sequence that is cleaved and degraded during insertion of the protein into the plasma membrane. They showed that the 70-kD polypeptide is the glycosylated form of the fetal brain-specific variant and that its EGF-like domain could be released into the extracellular medium where it could activate ERBB4 (600543).

Kao et al. (2010) isolated NRG3 cDNA from adult human hippocampus and whole brain. The full-length 720-residue protein has a molecular mass of 77.91 kD. Multiple other alternatively spliced NRG3 transcripts were identified that could be classified into 4 classes based on exon homology. Class I included the full-length protein and a deduced 696-residue protein with a molecular mass of 75 kD and a weaker 77-kD band. Class II variants showed homology to the fetal isoform described by Carteron et al. (2006). Class III variants were predicted to generate truncated proteins with molecular masses of approximately 46 kD that would lack the bioactive EGF domain. Class IV variants contained open reading frames of 500 to 524 amino acids. All of these transcripts were expressed in both fetal and adult human brain tissue.

Kao et al. (2010) found that the NRG3 gene contains 12 exons: exons 1 through 5 encode the extracellular portion of the protein, whereas exons 8 through 12 encode the cytoplasmic portion of the protein. Thirteen different NRG3 splice variants fitting into 4 different classes were identified in both fetal and adult human brain.

Using somatic cell hybrid analysis, Zhang et al. (1997) mapped the NRG3 gene to chromosome 10q22.

Using a tagged version of the NRG3 EGF-like domain, Zhang et al. (1997) demonstrated that NRG3 can bind to the extracellular domain of the ERBB4 receptor tyrosine kinase (600543), but not to the related family members ERBB2 (164870) or ERBB3 (190151). Using immunoprecipitation and Western blot analysis, Zhang et al. (1997) demonstrated that NRG3 binding stimulated tyrosine phosphorylation of ERBB4. The binding to ERBB4 can be competed by the NRG1 EGF-like domain, suggesting that the binding sites of NRG1 and NRG3 overlap. After treatment of a human breast cancer cell line with the recombinant NRG3 EGF domain, Zhang et al. (1997) detected a substantial increase in tyrosine phosphorylation of ERBB4 receptor.

Carteron et al. (2006) showed that NRG3 promoted the phosphorylation of Akt1 (164730) in a dose-dependent manner in serum-deprived C6 glioma cells. Recombinant NRG3 promoted survival of serum-starved cultured oligodendrocyte precursors and that inhibition of the PI3K pathway blocked the effect of NRG3 on oligodendrocyte-precursor survival.

Kao et al. (2010) found that expression of class I NRG3 isoforms containing the classic 5-prime exon 1 was significantly increased (about 40%) in the dorsolateral prefrontal cortex of individuals with schizophrenia compared to controls. Class IV NRG3 isoforms, containing exon 3 contiguous with exon 4, were also increased by about 50% in individuals with schizophrenia compared to controls. Class II and III transcripts did not show differences in expression. Kao et al. (2010) also demonstrated that the common T allele of rs10748842 in intron 1 of the NRG3 gene is located within a binding site for multiple transcription factors and was associated with increased expression of class II and III NRG3 transcripts in human brain tissue. Kao et al. (2010) suggested that differential regulation of NRG3 isoforms may affect neurodevelopmental pathways and play a role in the development of schizophrenia.

For a discussion of a possible association between variation in the NRG3 gene and schizophrenia, see SCZD11 (608078).

Green et al. (2010) published a draft sequence of the Neandertal genome. Comparisons of the Neandertal genome to the genomes of 5 present-day humans from different parts of the world identified a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. Green et al. (2010) identified a total of 212 regions containing putative selective sweeps. Mutations in several genes in regions of selective sweeps, including NRG3, DYRK1A (600855), CADPS2 (609978), and AUTS2 (607270), have been associated with disorders affecting cognitive capacities. Green et al. (2010) hypothesized that multiple genes involved in cognitive development were positively selected during the early history of modern humans. Green et al. (2010) also showed that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.