Alternative titles; symbols
HGNC Approved Gene Symbol: EFNA3
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:155,078,837-155,087,538 (from NCBI)
Proteins in the LERK subfamily of ligands, called ephrins, bind to members of the EPH group of receptor tyrosine kinases. The various ephrins are characterized by sequence similarities and the fact that they are attached to the cell membrane by glycosylphosphatidylinositol (GPI) anchors or by a single transmembrane domain (Cerretti et al., 1996). See 179610 for additional information on ephrins and the Eph receptor family.
Davis et al. (1994) cloned EFNA3, which they called EHK1L, from a human SH-SY5Y neuroblastoma cell line cDNA library. The deduced 234-amino acid protein contains an N-terminal signal sequence, followed by a predicted receptor tyrosine kinase-binding domain and a C-terminal hydrophobic tail predicted to bind glycophosphatidylinositol (GPI). Northern blot analysis of rat tissues detected high Ehk1l expression in all central nervous system regions examined and in embryonic brain. It was also expressed in skin, but not in any other nonneuronal tissues examined. EHK1L was expressed on the cell surface of transfected COS cells, and treatment of cells with phospholipase C (see 172420) released EHK1L, consistent with its membrane association via a GPI linkage.
Using the receptor tyrosine kinase HEK (EPHA3; 179611) as bait to screen a human T-lymphoma HSB-2 cDNA expression library, Kozlosky et al. (1995) cloned LERK3. The deduced 238-amino acid LERK3 protein has a predicted N-terminal signal sequence, an extracellular receptor-binding domain, a spacer region, and a hydrophobic C terminus. The receptor-binding domain has 3 N-glycosylation sites and 6 cysteines predicted to form disulfide bonds, and the C terminus shares structural similarity with GPI-linked proteins. Northern blot analysis detected LERK3 transcripts of 2.0 and 0.8 kb in human adult brain, skeletal muscle, spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood leukocytes. LERK3 was also expressed in embryonic heart, brain, lung, liver, and kidney, and embryonic brain expressed an additional 2.1-kb transcript.
Cerretti and Nelson (1998) reported that the mouse Efna3 gene has 5 exons. The gene structures of human EFNA2 (602756) and mouse Efna3, Efna4 (601380), and Efnb1 (300035) are conserved through the first 3 exons.
By fluorescence in situ hybridization, Cerretti et al. (1996) mapped the EPLG3 gene to a cluster on chromosome 1q21-q22, together with EPLG1 (EFNA1; 191164) and EPLG4 (EFNA4; 601380). By interspecific backcross analysis, they mapped the mouse EPLG3 homolog (Epl3) to the central region of mouse chromosome 3.
By expression cloning in COS cells, Davis et al. (1994) found that human B61 (EFNA1; 191164) and EHK1L bound to the receptor tyrosine kinase EHK1 (EPHA5; 600004), but not to ELK (EPHB1; 600600).
By analyzing binding kinetics, Kozlosky et al. (1995) found that LERK3 had a single class of binding sites for HEK, but a biphasic binding curve with high- and low-affinity binding components for ELK.
Communication between glial cells and neurons is believed to be a critical parameter of synaptic function via remodeling. Murai et al. (2003) localized the EphA4 tyrosine kinase receptor (602188) to dendritic spines of pyramidal neurons in the adult mouse hippocampus. The EphA4 ligand ephrin-A3 was localized to astrocytic processes that envelop spines. Activation of EphA4 by ephrin-A3 was found to induce spinal retraction and reduce spine density, and inhibiting the interaction distorted spine shape and organization. Murai et al. (2003) concluded that neuroglial repulsive cross-talk between the 2 molecules regulates the structure of synaptic connections.
To examine the roles of EphA receptors and ephrin-A ligands in neuronal migration in the neocortex, Torii et al. (2009) analyzed Efna1/Efna3/Efna5 (601535) triple-knockout mice. These genes account for almost all ephrin-A genes in the developing neocortex. Most analyses were performed at postnatal day 0 or embryonic stages before the establishment of potentially mistargeted, afferent, and efferent projections. Torii et al. (2009) showed that an EphA and ephrin A (Efna) signaling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns in the neocortex. In contrast to the relatively uniform labeling of the developing cortical plate by various molecular markers and retrograde tracers in wildtype mice, Torii et al. (2009) found alternating labeling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and Efnas during neuronal migration. Torii et al. (2009) concluded that this theretofore unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization.
Cang et al. (2005) created Efna2/Efna3/Efna5 (601535) triple-knockout (TKO) mice and found that the thalamocortical projections from the dorsal lateral geniculate nucleus to the visual cortex showed abnormal topographic mapping. Functional imaging in Efna-TKO mice revealed that the primary visual area (V1) was rotated and shifted medially and that the internal organization of the visuotopic map was disrupted. Cang et al. (2005) concluded that EFNAs guide the formation of functional maps in the visual cortex.
Cang, J., Kaneko, M., Yamada, J., Woods, G., Stryker, M. P., Feldheim, D. A. Ephrin-As guide the formation of functional maps in the visual cortex. Neuron 48: 577-589, 2005. [PubMed: 16301175] [Full Text: https://doi.org/10.1016/j.neuron.2005.10.026]
Cerretti, D. P., Lyman, S. D., Kozlosky, C. J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Valentine, V., Kirstein, M. N., Shapiro, D. N., Morris, S. W. The genes encoding the Eph-related receptor tyrosine kinase ligands LERK-1 (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are clustered on human chromosome 1 and mouse chromosome 3. Genomics 33: 277-282, 1996. [PubMed: 8660976] [Full Text: https://doi.org/10.1006/geno.1996.0192]
Cerretti, D. P., Nelson, N. Characterization of the genes for mouse LERK-3/Ephrin-A3 (Epl3), mouse LERK-4/Ephrin-A4 (Epl4), and human LERK-6/Ephrin-A2 (EPLG6): conservation of intron/exon structure. Genomics 47: 131-135, 1998. [PubMed: 9465306] [Full Text: https://doi.org/10.1006/geno.1997.5088]
Davis, S., Gale, N. W., Aldrich, T. H., Maisonpierre, P. C., Lhotak, V., Pawson, T., Goldfarb, M., Yancopoulos, G. D. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266: 816-819, 1994. [PubMed: 7973638] [Full Text: https://doi.org/10.1126/science.7973638]
Kozlosky, C. J., Maraskovsky, E., McGrew, J. T., VandenBos, T., Teepe, M., Lyman, S. D., Srinivasan, S., Fletcher, F. A., Gayle, R. B., III, Cerretti, D. P., Beckmann, M. P. Ligands for the receptor tyrosine kinases hek and elk: isolation of cDNAs encoding a family of proteins. Oncogene 10: 299-306, 1995. [PubMed: 7838529]
Murai, K. K., Nguyen, L. N., Irie, F., Yamaguchi, Y., Pasquale, E. B. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nature Neurosci. 6: 153-160, 2003. [PubMed: 12496762] [Full Text: https://doi.org/10.1038/nn994]
Torii, M., Hashimoto-Torii, K., Levitt, P., Rakic, P. Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461: 524-528, 2009. Note: Erratum: Nature 462: 674 only, 2009. [PubMed: 19759535] [Full Text: https://doi.org/10.1038/nature08362]