Alternative titles; symbols
HGNC Approved Gene Symbol: EFNA5
Cytogenetic location: 5q21.3 Genomic coordinates (GRCh38): 5:107,376,894-107,670,937 (from NCBI)
EFNA5 belongs to the LERK subfamily of ligands, called ephrins, which 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) linkages or by a single transmembrane domain (Cerretti et al., 1996).
See 179610 for additional information on ephrins and the Eph receptor family.
By sequencing proteins from BT20 human breast carcinoma and HeLa cells that interacted with the receptor tyrosine kinase REK7 (EPHA5; 600004), followed by PCR and screening a human fetal brain cDNA library, Winslow et al. (1995) cloned EFNA5, which they called AL1. The deduced 228-amino acid protein has an N-terminal signal peptide, followed by a receptor-binding domain and a hydrophobic C-terminal domain predicted to function as a cleavage/attachment site for GPI addition. Northern blot analysis detected transcripts of approximately 7.4 and 6 kb that were highly expressed in human brain, heart, placenta, lung, and kidney, with lower expression in other tissues. AL1 was highly expressed throughout brain. It was more highly expressed in rat astrocytes than in neurons.
By somatic cell hybrid analysis and FISH, Cerretti et al. (1996) mapped the EFNA5 gene to chromosome 5q21. By Southern blot analysis, they mapped the mouse Efna5 gene to a region of chromosome 17 that shows homology of synteny to human chromosome 5q21.
Winslow et al. (1995) found that HEK293 cells transiently expressing AL1 activated endogenous Rek7 expressed on the surface of cocultured rat cortical neurons. They presented evidence suggesting that AL1 may be involved in axon bundle formation. Drescher et al. (1995) also suggested that the EFNA5 protein, which they called RAGS, may be involved in axon guidance.
RAGS and ELF1 (189973), both ligands for EPH-related receptor tyrosine kinases, have been implicated in the control of development of the retinotectal projection. Both molecules are expressed in overlapping gradients in the tectum, the target area of the retinal ganglion cell axons. In 2 in vitro assays using developing chick tectum, Monschau et al. (1997) showed that ELF1 has a repellent axon guidance function for temporal, but apparently not for nasal, axons. RAGS, on the other hand, is repellent for both types of axons, though to different degrees.
Himanen et al. (2004) found that ephrin-A5 binds to the EphB2 receptor (600997), leading to receptor clustering, autophosphorylation, and initiation of downstream signaling. Ephrin-A5 induced EphB2-mediated growth cone collapse and neurite retraction in a model system. X-ray crystallography confirmed the interaction and showed that the ephrin-A5-EphB2 complex is a heterodimer. Himanen et al. (2004) emphasized the unexpected finding of crosstalk between A- and B-subclass Eph receptors and ephrins.
By RT-PCR and confocal microscopy analysis, Konstantinova et al. (2007) demonstrated that mouse and human pancreatic beta cells expressed ephrin-A5 and EPHA5 (600004), suggesting that ephrin-A-EPHA bidirectional signaling may occur between adjacent beta cells. Mouse islet cells lacking ephrin-A5 had increased basal insulin secretion and did not secrete insulin in response to glucose stimulation. Pancreatic islet cells stimulated with Epha5 had increased basal and glucose-stimulated insulin secretion, whereas ephrin-A5-stimulated cells had decreased glucose-stimulated insulin secretion. Konstantinova et al. (2007) concluded that beta-cell communication through EPHA5 and ephrin-A5 in pancreatic islets affects basal and glucose-stimulated insulin secretion to improve glucose homeostasis.
Using immunoprecipitation and confocal microscopy, Lim et al. (2008) demonstrated that nerve growth factor receptor (NGFR; 162010) and ephrin-As, including Efna2 (602756) and Efna5, 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.
To examine the roles of EphA receptors and ephrin-A ligands in neuronal migration in the neocortex, Torii et al. (2009) analyzed Efna1 (191164)/Efna3 (601381)/Efna5 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.
Frisen et al. (1998) developed Efna5-null mice. The majority of Efna5-null mice developed to adulthood, were morphologically intact, and had normal anterior-posterior patterning of the midbrain. However, within the superior colliculus (SC), retinal axons established and maintained dense arborizations at topographically incorrect sites that correlated with locations of low expression of the related ligand, Efna2 (602756). In addition, retinal axons transiently overshot the SC and extended aberrantly into the inferior colliculus. Frisen et al. (1998) concluded that the repulsive effect of local Efna5 expression is required for the proper guidance and mapping of retinal axons in the midbrain.
Ligand binding to an Eph receptor results in tyrosine phosphorylation of the kinase domain, and repulsion of axonal growth cones and migrating cells. Holmberg et al. (2000) reported that a subpopulation (17%) of ephrin-A5-null mice displayed neural tube defects resembling anencephaly in man. Similar to human, 71% of affected ephrin-A5-null embryos were female. The phenotype is caused by the failure of the neural folds to fuse in the dorsal midline, suggesting that ephrin-A5, in addition to its involvement in cell repulsion, can participate in cell adhesion. During neurulation, ephrin-A5 is coexpressed with its cognate receptor EphA7 (602190) in cells at the edges of the dorsal neural folds. Three different EphA7 splice variants, a full-length form and 2 truncated versions lacking kinase domains, are expressed in the neural folds. Coexpression of an endogenously expressed truncated form of EphA7 suppresses tyrosine phosphorylation of the full-length EphA7 receptor and shifts the cellular response from repulsion to adhesion in vitro. Holmberg et al. (2000) concluded that alternative usage of different splice forms of a tyrosine kinase receptor can mediate cellular adhesion or repulsion during embryonic development.
Cang et al. (2005) created Efna2/Efna3 (601381)/Efna5 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.
Cooper et al. (2008) generated Efna5 -/- mice and observed lens fiber cells that were rounded and irregular in cross-section, in contrast to the normal hexagonal appearance in wildtype lenses. Cataracts eventually developed in 87% of the Efna5-null mice. Studies in 293T cells demonstrated that EFNA5 interacted with the EPHA2 (176946) receptor to regulate the adherens junction complex by enhancing recruitment of beta-catenin (116806) to N-cadherin (114020). Cooper et al. (2008) concluded that the EPH receptors and their ligands are critical regulators of lens development and maintenance.
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., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Kuefer, M. U., Valentine, V., Shapiro, D. N., Cui, X., Morris, S. W. The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome 17. Genomics 35: 376-379, 1996. [PubMed: 8661153] [Full Text: https://doi.org/10.1006/geno.1996.0371]
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]
Cooper, M. A., Son, A. I., Komlos, D., Sun, Y., Kleiman, N. J., Zhou, R. Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract. Proc. Nat. Acad. Sci. 105: 16620-16625, 2008. [PubMed: 18948590] [Full Text: https://doi.org/10.1073/pnas.0808987105]
Drescher, U., Kremoser, C., Handwerker, C., Loschinger, J., Noda, M., Bonhoeffer, F. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82: 359-370, 1995. [PubMed: 7634326] [Full Text: https://doi.org/10.1016/0092-8674(95)90425-5]
Frisen, J., Yates, P. A., McLaughlin, T., Friedman, G. C., O'Leary, D. D. M., Barbacid, M. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20: 235-243, 1998. [PubMed: 9491985] [Full Text: https://doi.org/10.1016/s0896-6273(00)80452-3]
Himanen, J.-P., Chumley, M. J., Lackmann, M., Li, C., Barton, W. A., Jeffrey, P. D., Vearing, C., Geleick, D., Feldheim, D. A., Boyd, A. W., Henkemeyer, M., Nikolov, D. B. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nature Neurosci. 7: 501-509, 2004. [PubMed: 15107857] [Full Text: https://doi.org/10.1038/nn1237]
Holmberg, J., Clarke, D. L., Frisen, J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408: 203-206, 2000. [PubMed: 11089974] [Full Text: https://doi.org/10.1038/35041577]
Konstantinova, I., Nikolova, G., Ohara-Imaizumi, M., Meda, P., Kucera, T., Zarbalis, K., Wurst, W., Nagamatsu, S., Lammert, E. EphA-ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets. Cell 129: 359-370, 2007. [PubMed: 17448994] [Full Text: https://doi.org/10.1016/j.cell.2007.02.044]
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]
Monschau, B., Kremoser, C., Ohta, K., Tanaka, H., Kaneko, T., Yamada, T., Handwerker, C., Hornberger, M. R., Loschinger, J., Pasquale, E. B., Siever, D. A., Verderame, M. F., Muller, B. K., Bonhoeffer, F., Drescher, U. Shared and distinct functions of RAGS and ELF-1 in guiding retinal axons. EMBO J. 16: 1258-1267, 1997. [PubMed: 9135142] [Full Text: https://doi.org/10.1093/emboj/16.6.1258]
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]
Winslow, J. W., Moran, P., Valverde, J., Shih, A., Yuan, J. Q., Wong, S. C., Tsai, S. P., Goddard, A., Henzel, W. J., Hefti, F., Beck, K. D., Caras, I. W. Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation. Neuron 14: 973-981, 1995. [PubMed: 7748564] [Full Text: https://doi.org/10.1016/0896-6273(95)90335-6]