Alternative titles; symbols
HGNC Approved Gene Symbol: LYNX1
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:142,771,197-142,777,872 (from NCBI)
The LYNX1 gene encodes a protein that shares characteristics with toxins that bind and inhibit nicotinic acetylcholine receptors (nAChR; see, e.g., CHRNA1, 100690) (Miwa et al., 1999). Components of snake venoms often have structural and functional mammalian homologs. For example, hemolytic snake venom toxins are related to cellular phospholipases (e.g., PLA2G1B; 172410), and snake sarafotoxins may be related to vertebrate endothelins (e.g., EDN1; 131240). The elapid venom alpha-bungarotoxin also binds to and inhibits nAChR.
By screening for central nervous system-specific, developmentally regulated cDNAs in mouse, Miwa et al. (1999) identified a cDNA encoding GC26, which was expressed in mouse cerebellum. Sequence analysis predicted that the 116-amino acid protein contains a signal sequence at its N terminus, a cysteine-rich consensus motif characteristic of LY6 family proteins (e.g., CD59; 107271) and snake alpha-neurotoxins, and an asparagine/GPI anchor motif at its C terminus. The overall structure of GC26 is similar to that of LY6 family proteins and snake alpha-neurotoxins, and Miwa et al. (1999) redesignated the protein 'Ly6/neurotoxin-1,' or Lynx1. A partial sequence encoding a human Lynx1 homolog has been identified (GenBank AF321824). Northern blot analysis revealed predominant expression of Lynx1 in mouse brain. In situ hybridization analysis showed Lynx1 expression in neurons in multiple brain structures. Immunocytochemistry demonstrated expression of Lynx1 in neuronal soma and proximal dendrites.
Using microarray analysis to identify ESTs expressed predominantly in the skin of patients with psoriasis vulgaris (see 177900), followed by PCR and RACE of cultured keratinocyte cDNA libraries, Tsuji et al. (2003) cloned LYNX1, which they called SLURP2. The deduced 97-amino acid protein contains a signal peptide and 10 conserved cysteine residues with a spacing pattern characteristic of the LY6 superfamily, but it does not have the GPI anchor or transmembrane domains found in membrane-bound LY6 proteins. Northern blot analysis detected a 0.6-kb transcript in esophagus and a 1.6-kb transcript in stomach and duodenum. No expression was detected in other tissues examined, including skin. RT-PCR detected abundant LYNX1 expression in cervix and esophagus, with lower expression in adult and fetal skin and keratinocytes. Weak expression was detected in brain, lung, stomach, small intestine, colon, rectum, uterus, and thymus. No expression was detected in spleen and bone marrow. Real-time quantitative RT-PCR analysis detected a 3.8- to 2.8-fold increase in LYNX1 expression in lesional skin from 5 psoriasis patients compared with nonlesional skin or normal skin.
Functional analysis by Miwa et al. (1999) indicated that Lynx1 is not a ligand or neurotransmitter but has the capacity to enhance nicotinic acetylcholine receptor function in the presence of acetylcholine.
Morishita et al. (2010) identified an increase in expression of Lynx1 protein in mice that prevented plasticity in the primary visual cortex late in life. Removal of this molecular brake enhanced nicotinic acetylcholine receptor signaling. Lynx1 expression thus maintains stability of mature cortical networks in the presence of cholinergic innervation. Morishita et al. (2010) concluded that modulating the balance between excitatory and inhibitory circuits reactivates visual plasticity.
Tsuji et al. (2003) determined that the LYNX1 gene contains 3 exons and spans about 5.6 kb. The promoter region contains 3 Sp1 (189906)- and 2 AP1 (165160)-binding sites, as well as single sites for E2F (189971) and GATA3 (131320). It lacks TATA and CAAT consensus sequences. There are 2 major transcriptional initiation sites.
By genomic sequence analysis, Tsuji et al. (2003) mapped the LYNX1 gene to chromosome 8q24.3. Southern blot analysis indicated that LYNX1 is a single-copy gene.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including LYNX1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
Miwa et al. (2006) found that Lynx1 -/- mice showed no gross abnormalities in size, viability, CNS morphology, or longevity compared to wildtype mice. However, Lynx1-null mice showed increased learning and memory in a fear-conditioned paradigm and displayed increased sensitivity to nicotine in motor tasks compared to wildtype. Neurons from Lynx1-null mice showed heightened sensitivity and increased intracellular calcium levels in response to nicotine. Loss of Lynx1 decreased receptor desensitization and enhanced synaptic efficacy. Mutant neurons were also more sensitive to excitotoxic insult, and Lynx1 mutant mice exhibited age-dependent degeneration that was exacerbated by nicotine and rescued by null mutations in nAChR subunits. These data supported the hypotheses that Lynx1 normally decreases activity of nAChRs and that deletion of Lynx1 shifts the balance in favor of increased neuronal activity and synaptic plasticity. But the short-term benefits of the loss of Lynx1 were counterbalanced by an increased vulnerability of Lynx1 mutant neurons to glutamate toxicity and by loss of nicotine's neuroprotective effect on these cells. Miwa et al. (2006) concluded that Lynx1 modulates nAChR function to maintain low sensitivity and plays a critical role in maintaining a balance between the beneficial effects of short-term nAChR activation and the degenerative effects of chronic receptor activation.
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. Accelerated evolution of nervous system genes in the origin of Homo sapiens. Cell 119: 1027-1040, 2004. [PubMed: 15620360] [Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
Miwa, J. M., Ibanez-Tallon, I., Crabtree, G. W., Sanchez, R., Sali, A., Role, L. W., Heintz, N. Lynx1, an endogenous toxin-like modulator of nicotinic acetylcholine receptors in the mammalian CNS. Neuron 23: 105-114, 1999. [PubMed: 10402197] [Full Text: https://doi.org/10.1016/s0896-6273(00)80757-6]
Miwa, J. M., Stevens, T. R., King, S. L., Caldarone, B. J., Ibanez-Tallon, I., Xiao, C., Fitzsimonds, R. M., Pavlides, C., Lester, H. A., Picciotto, M. R., Heintz, N. The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron 51: 587-600, 2006. [PubMed: 16950157] [Full Text: https://doi.org/10.1016/j.neuron.2006.07.025]
Morishita, H., Miwa, J. M., Heintz, N., Hensch, T. K. Lynx1, a cholinergic brake, limits plasticity in adult visual cortex. Science 330: 1238-1240, 2010. [PubMed: 21071629] [Full Text: https://doi.org/10.1126/science.1195320]
Tsuji, H., Okamoto, K., Matsuzaka, Y., Iizuka, H., Tamiya, G., Inoko, H. SLURP-2, a novel member of the human Ly-6 superfamily that is upregulated in psoriasis vulgaris. Genomics 81: 26-33, 2003. [PubMed: 12573258] [Full Text: https://doi.org/10.1016/s0888-7543(02)00025-3]