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Gene Review

Efna2  -  ephrin A2

Mus musculus

Synonyms: CEK7-L, CEK7-ligand, CEK7L, Cek7-L, ELF-1, ...
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Disease relevance of Efna2

  • During dental trigeminal axon pathfinding (embryonic days 12.5-13.5), ephrin-A2, ephrin-A4, and ephrin-A5 were evenly distributed in the trigeminal ganglion, whereas EphA7 was expressed in a subset of ganglion cells [1].
  • As in the LGd, retinal axons from each eye terminate in discrete eye-specific zones in the MGN of rewired wild-type and ephrin-A2/A5 knockout mice [2].
  • A tailored ELF-1 blocking peptide, containing a 12-amino acid HIV-1 TAT protein, readily crosses the cell membrane and enters into the nucleus of endothelial cells, leading to a marked reduction in the expression of ELF-1 gene targets including Tie2 and endothelial nitric oxide synthase [3].
  • Methods: Female nude mice injected intraperitoneally with HeyA8 ovarian cancer cells were treated with either docetaxel alone or in combination with anti-angiogenic agents (AEE788-dual VEGFR and EGFR antagonist or EA5-monoclonal antibody against ephrin A2) [4].

High impact information on Efna2

  • The expression domains of ELF-1, Mek4 and Sek indicate potential roles in embryonic patterning [5].
  • In cell lines and embryos, ELF-1 is membrane bound by a phosphatidylinositol tail, a feature that may account for unique biological functions [5].
  • The identification of ephrin-A2 and EphA7 as negative regulators of progenitor cell proliferation reveals a novel mechanism to control cell numbers in the brain [6].
  • We here report the identification of an additional mechanism to control cell number in the brain: EphA7 induces ephrin-A2 reverse signaling, which negatively regulates neural progenitor cell proliferation [6].
  • Here we found that in mice deficient for ephrin-A2, ephrin-A3 and ephrin-A5, eye-specific inputs segregated but the shape and location of eye-specific layers were profoundly disrupted [7].

Biological context of Efna2

  • Cells in the neural stem cell niche in the adult brain proliferate more and have a shorter cell cycle in mice lacking ephrin-A2 [6].
  • Subsequent molecular analysis demonstrated that both the -8 enhancer and the promoter depend on conserved Ets sites, which were bound in endothelial cells in vivo by Fli-1, Erg, and Elf-1 [8].
  • In the present study, we proved the upregulation of ephrin-A2 in the denervated areas of the ipsilateral hippocampus following PP transections [9].
  • Only the ephrin-A2 probe was tested on tadpole brain, yielding an appropriately graded expression pattern similar to the adult [10].
  • Transactivation and expression studies support the hypothesis that Elf-1 activates TdT transcription in immature T and B cells [11].

Anatomical context of Efna2

  • Here, we map the visual cortex (V1) in mice deficient for ephrin-A2, -A3, and -A5 functionally, using intrinsic signal optical imaging and microelectrode recording, and structurally, by anatomical tracing of thalamocortical projections [12].
  • Here, we show complementary expression and binding for the receptor EphA5 in mouse retina and its ligands ephrin-A2 and ephrin-A5 in multiple retinal targets, including the major forebrain target, the dorsal lateral geniculate nucleus (dLGN) [13].
  • EphA2, 3, and 4 receptors and one of their cognate ligands, ephrin-A2, are expressed by cells in the subventricular zone and ganglionic eminence of the embryonic day 14.5 telencephalon and by neural precursor cells in vitro [14].
  • Ephrin-A2 and -A5 influence patterning of normal and novel retinal projections to the thalamus: conserved mapping mechanisms in visual and auditory thalamic targets [2].
  • Many studies have demonstrated the involvement of the EphA family of receptor tyrosine kinases and their ligands, ephrin-A2 and -A5, in the development of the temporonasal axis of the retinotectal/collicular map, but the role of these molecules in optic nerve regeneration has not been well studied [15].

Associations of Efna2 with chemical compounds


Physical interactions of Efna2


Regulatory relationships of Efna2

  • We present strong evidence that ELF-1 is highly expressed in B-cells and is one of two major factors specifically interacting with the murine IgH enhancer pi site in B-cell nuclear extracts [17].

Other interactions of Efna2

  • Elf-1 and B61 bind to the three full-length MDK1 isoforms with similar dissociation constants [18].
  • It was previously shown that ephrin-A2, -A3 and -A5 bind to, and activate the EphA8 receptor tyrosine kinase, respectively [19].
  • Both the model promoter and the macrophage-specific mouse and human c-fms promoters were activated in RAW264 cells by other Ets family transcription factors, Ets-2 and Elf-1 [20].
  • Transcriptional regulation of the stem cell leukemia gene by PU.1 and Elf-1 [21].
  • At the protein level, MITF, SCL, GATA-2, Elf-1 and c-fos were clearly detectable in sMCs [22].


  1. Expression of ephrin-A ligands and EphA receptors in the developing mouse tooth and its supporting tissues. Luukko, K., Løes, S., Kvinnsland, I.H., Kettunen, P. Cell Tissue Res. (2005) [Pubmed]
  2. Ephrin-A2 and -A5 influence patterning of normal and novel retinal projections to the thalamus: conserved mapping mechanisms in visual and auditory thalamic targets. Ellsworth, C.A., Lyckman, A.W., Feldheim, D.A., Flanagan, J.G., Sur, M. J. Comp. Neurol. (2005) [Pubmed]
  3. Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Huang, X., Brown, C., Ni, W., Maynard, E., Rigby, A.C., Oettgen, P. Blood (2006) [Pubmed]
  4. Circulating Cell-Free DNA: A Novel Biomarker for Response to Therapy in Ovarian Carcinoma. Kamat, A.A., Bischoff, F.Z., Dang, D., Baldwin, M.F., Han, L.Y., Lin, Y.G., Merritt, W.M., Landen, C.N., Lu, C., Gershenson, D.M., Simpson, J.L., Sood, A.K. Cancer Biol. Ther. (2006) [Pubmed]
  5. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cheng, H.J., Flanagan, J.G. Cell (1994) [Pubmed]
  6. Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Holmberg, J., Armulik, A., Senti, K.A., Edoff, K., Spalding, K., Momma, S., Cassidy, R., Flanagan, J.G., Frisén, J. Genes Dev. (2005) [Pubmed]
  7. Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping. Pfeiffenberger, C., Cutforth, T., Woods, G., Yamada, J., Rentería, R.C., Copenhagen, D.R., Flanagan, J.G., Feldheim, D.A. Nat. Neurosci. (2005) [Pubmed]
  8. Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a -8-kb enhancer. Pimanda, J.E., Chan, W.Y., Donaldson, I.J., Bowen, M., Green, A.R., Göttgens, B. Blood (2006) [Pubmed]
  9. Denervation-induced spatiotemporal upregulation of ephrin-A2 in the mouse hippocampus after transections of the perforant path. Wang, Y., Ni, Z.M., Zhou, C.F. FEBS Lett. (2005) [Pubmed]
  10. Partial nucleotide sequences and expression patterns of frog (Rana pipiens) ephrin-A2 and ephrin-A5 mRNA. Yagita, Y., Barjis, I., Hecht, M., Bach, H., Feldheim, D.A., Scalia, F. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  11. A potential role for Elf-1 in terminal transferase gene regulation. Ernst, P., Hahm, K., Trinh, L., Davis, J.N., Roussel, M.F., Turck, C.W., Smale, S.T. Mol. Cell. Biol. (1996) [Pubmed]
  12. Ephrin-as guide the formation of functional maps in the visual cortex. Cang, J., Kaneko, M., Yamada, J., Woods, G., Stryker, M.P., Feldheim, D.A. Neuron (2005) [Pubmed]
  13. Topographic guidance labels in a sensory projection to the forebrain. Feldheim, D.A., Vanderhaeghen, P., Hansen, M.J., Frisén, J., Lu, Q., Barbacid, M., Flanagan, J.G. Neuron (1998) [Pubmed]
  14. EphA receptors direct the differentiation of mammalian neural precursor cells through a mitogen-activated protein kinase-dependent pathway. Aoki, M., Yamashita, T., Tohyama, M. J. Biol. Chem. (2004) [Pubmed]
  15. Persistence of graded EphA/Ephrin-A expression in the adult frog visual system. Bach, H., Feldheim, D.A., Flanagan, J.G., Scalia, F. J. Comp. Neurol. (2003) [Pubmed]
  16. Roles of Ets proteins, NF-kappa B and nocodazole in regulating induction of transcription of mouse germline Ig alpha RNA by transforming growth factor-beta 1. Shi, M.J., Park, S.R., Kim, P.H., Stavnezer, J. Int. Immunol. (2001) [Pubmed]
  17. ELF-1 interacts with and transactivates the IgH enhancer pi site. Akbarali, Y., Oettgen, P., Boltax, J., Libermann, T.A. J. Biol. Chem. (1996) [Pubmed]
  18. Identification of Elf-1 and B61 as high affinity ligands for the receptor tyrosine kinase MDK1. Ciossek, T., Ullrich, A. Oncogene (1997) [Pubmed]
  19. Characterization of ephrin-A1 and ephrin-A4 as ligands for the EphA8 receptor protein tyrosine kinase. Choi, S., Jeong, J., Kim, T., Park, S. Mol. Cells (1999) [Pubmed]
  20. Interaction between PU.1 and another Ets family transcription factor promotes macrophage-specific Basal transcription initiation. Ross, I.L., Yue, X., Ostrowski, M.C., Hume, D.A. J. Biol. Chem. (1998) [Pubmed]
  21. Transcriptional regulation of the stem cell leukemia gene by PU.1 and Elf-1. Bockamp, E.O., Fordham, J.L., Göttgens, B., Murrell, A.M., Sanchez, M.J., Green, A.R. J. Biol. Chem. (1998) [Pubmed]
  22. The transcription factor profile of human mast cells in comparison with monocytes and granulocytes. Babina, M., Schülke, Y., Kirchhof, L., Guhl, S., Franke, R., Böhm, S., Zuberbier, T., Henz, B.M., Gombart, A.F. Cell. Mol. Life Sci. (2005) [Pubmed]
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