Alternative titles; symbols
HGNC Approved Gene Symbol: EFNA2
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:1,284,227-1,301,431 (from NCBI)
See 179610 for background on ephrins and the Eph receptor family.
By screening a human genomic library with a mouse ephrin-A2 (Efna2) cDNA, Cerretti and Nelson (1998) isolated the genomic sequence of EFNA2. The predicted 213-amino acid EFNA2 protein is composed of a signal sequence, a receptor-binding region, a spacer region, and a hydrophobic region.
By screening a fetal brain cDNA library with a fragment of human EFNA4 (601380), Aasheim et al. (1998) cloned a human EFNA2 cDNA. The deduced 214-amino acid protein contained a signal sequence, 3 potential N-glycosylation sites, and a hydrophilic C terminus including a GPI linkage signal. Northern blot analysis of human tissues detected a single 2.4-kb transcript in fetal intestine and brain and in adult colon, small intestine, and lung. During mouse embryogenesis, Efna2 is first detected in the dorsal region of the presumptive midbrain at embryonic (E) day 8. By E9, there are high levels of Efna2 expression in the midbrain and lower levels in the dorsal anterior hindbrain. Between E8.5 and E11, it is expressed in the first and second branchial arches, somites, and limb buds.
Cerretti and Nelson (1998) determined that the EFNA2 gene has 4 exons; its structure is identical to the gene structures of mouse Efna3 (601381), Efna4, and Efnb1 (300035) through the first 3 exons.
Although ephrins form a high-affinity multivalent complex with their receptors present on axons, axons can be rapidly repelled rather than being bound. Hattori et al. (2000) showed that ephrin-A2 forms a stable complex with the metalloproteinase Kuzbanian (ADAM10; 602192), involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. The cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. Hattori et al. (2000) concluded that their studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling.
Using immunoprecipitation and confocal microscopy, Lim et al. (2008) demonstrated that nerve growth factor receptor (NGFR; 162010) and ephrin-As, including Efna2 and Efna5 (601535), colocalized within caveolae along mouse retinal axons and formed a complex required for Fyn (137025) phosphorylation upon binding EphAs, activating a signaling pathway that led to cytoskeletal changes. Retinal axons repulsed EphAs by ephrin-A reverse signaling in an Ngfr-dependent manner. Mice lacking Ngfr constitutively or specifically in retina had aberrant anterior shifts in retinal axon terminations in the superior colliculus, consistent with diminished repellent activity mediated by graded collicular EphAs. Lim et al. (2008) concluded that NGFR is a signaling partner for EPHAs and that the EPHA/NGFR complex reverse signals to mediate axon repulsion required for guidance and mapping.
Using PCR-based screening of genomic DNA from human/rodent hybrid cell lines, Aasheim et al. (1998) mapped the EFNA2 gene to chromosome 19. By FISH, they narrowed the location to 19p13.3.
Cang et al. (2005) created Efna2/Efna3 (601381)/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.
Yu et al. (2013) found that knockout of mouse Efna2, but not Efna3, enhanced elimination of dendritic spines from cortical pyramidal neurons during adolescent development, leading to reduced total number of spines in the adult. Sensory experience and NMDA receptors were required to elevate spine elimination in adolescent Efna2 -/- mice. Yu et al. (2013) also found that Efna colocalized with glial glutamate transporters Glast (SLC1A3; 600111) and Glt1 (SLC1A2; 600300) in wildtype mice. These transporters were downregulated in Efna2 -/- mice, resulting in reduced glial glutamate uptake and increased synaptic glutamate content. Pharmacologic inhibition of glial glutamate uptake in wildtype mice also promoted spine elimination.
Aasheim, H.-C., Pedeutour, F., Grosgeorge, J., Logtenberg, T. Cloning, chromosomal mapping, and tissue expression of the gene encoding the human Eph-family kinase ligand ephrin-A2. Biochem. Biophys. Res. Commun. 252: 378-382, 1998. [PubMed: 9826538] [Full Text: https://doi.org/10.1006/bbrc.1998.9618]
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., 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]
Hattori, M., Osterfield, M., Flanagan, J. G. Regulated cleavage of a contact-mediated axon repellent. Science 289: 1360-1365, 2000. [PubMed: 10958785] [Full Text: https://doi.org/10.1126/science.289.5483.1360]
Lim, Y.-S., McLaughlin, T., Sung, T.-C., Santiago, A., Lee, K.-F., O'Leary, D. D. M. p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59: 746-758, 2008. [PubMed: 18786358] [Full Text: https://doi.org/10.1016/j.neuron.2008.07.032]
Yu, X., Wang, G., Gilmore, A., Yee, A. X., Li, X., Xu, T., Smith, S. J., Chen, L., Zuo, Y. Accelerated experience-dependent pruning of cortical synapses in ephrin-A2 knockout mice. Neuron 80: 64-71, 2013. [PubMed: 24094103] [Full Text: https://doi.org/10.1016/j.neuron.2013.07.014]