Alternative titles; symbols
HGNC Approved Gene Symbol: EPHA4
Cytogenetic location: 2q36.1 Genomic coordinates (GRCh38) : 2:221,418,027-221,574,202 (from NCBI)
Receptor protein tyrosine kinases (PTKs) are a structurally related superfamily of proteins. These receptors are characterized by 3 functional domains: an intracellular tyrosine kinase catalytic domain, a single membrane-spanning domain, and an extracellular ligand-binding domain. Binding of ligand to a receptor PTK causes receptor dimerization, autophosphorylation, and the initiation of a phosphorylation cascade culminating in a biologic response by the cell. The EPH/ELK subfamily of receptor PTKs includes EPHA3 (179611) and EPHB2 (600997). See 179610 for additional background on Eph receptors and their ligands, the ephrins.
Fox et al. (1995) used degenerate PCR and library screening to identify members of the EPH/ELK family in human fetal brain. They identified 3 novel genes: HEK7 (EPHA5; 600004), HEK8, and HEK11 (EPHA7; 602190). HEK8 encodes a 986-amino acid polypeptide. Northern blot analysis of human tissues revealed that HEK8 is widely expressed with multiple transcript sizes.
The rat homolog of HEK8 was described by Lai and Lemke (1991), the mouse homolog by Gilardi-Hebenstreit et al. (1992), and the chicken homolog by Sajjadi and Pasquale (1993).
Using immunohistochemical analysis of the developing mouse hindbrain, Cowan et al. (2000) detected Epha4 expression in hindbrain and floor plate, including axons crossing the midline.
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 to dendritic spines of pyramidal neurons in the adult mouse hippocampus. The EphA4 ligand ephrin-A3 (601381) 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.
Local circuits in the spinal cord that generate locomotion are termed central pattern generators. These provide coordinated bilateral control over the normal limb alternation that underlies walking. Isolated spinal cords from mice lacking either the EphA4 receptor or its ligand ephrin B3 (602297) have lost left-right limb alternation and instead exhibit synchrony. Kullander et al. (2003) identified EphA4-positive neurons as an excitatory component of the locomotor central pattern generator. Kullander et al. (2003) concluded that dramatic locomotor changes can occur as a consequence of local genetic rewiring and identified genes required for the development of normal locomotor behavior.
Ephrins and their receptors play critical roles in axon guidance and growth cone collapse by regulating small Rho GTPases. Shi et al. (2007) showed that alpha-2-chimerin (118423) was required for Epha4-dependent growth cone collapse. Prominent expression of alpha-2-chimerin was detected in rat brain and cortical neurons and was enriched in postsynaptic density fractions. The SH2 domain of alpha-2-chimerin interacted specifically with Epha4 in rat brain in a kinase-dependent manner. Ephrin-A1 (EFNA1; 191164)-stimulated activation of Epha4 resulted in phosphorylation of alpha-2-chimerin and increased alpha-2-chimerin GAP activity toward Rac1 (602048), which was required for Epha4-dependent growth cone collapse.
Gallarda et al. (2008) reported that, within axial nerves, establishment of discrete afferent and efferent pathways depends on coordinate signaling between coextending sensory and motor projections. These heterotypic axon-axon interactions require motor axonal EphA3 (179611)/EphA4 receptor tyrosine kinases activated by cognate sensory axonal ephrin-A ligands. Genetic elimination of transaxonal ephrin-A-to-EphA signaling in mice triggered drastic motorsensory miswiring, culminating in functional efferents within proximal afferent pathways. Gallarda et al. (2008) concluded that effective assembly of a key circuit underlying motor behaviors thus critically depends on transaxonal signaling interactions resolving motor and sensory projections into discrete pathways.
Dottori et al. (1998) generated EphA4-null mice by gene targeting. The mice possessed defects in the corticospinal tract and anterior commissure. As EphA4 expression was not detected in the corticospinal tract, Dottori et al. (1998) proposed a model in which an ephrin ligand on the axons senses EphA4 on spinal cord cells surrounding the corticospinal tract. Leighton et al. (2001) revisited the issue of whether EphA4 has a ligand function by analyzing an EphA4 mutant generated by a modified gene-trapping method involving the use of PLAP (171800) as an axonal marker. Like the targeted EphA4 mutants, homozygous EphA4 gene-trap mice exhibited a hopping kangaroo gait and had guidance defects in the corticospinal tract and anterior commissure. However, Leighton et al. (2001) found evidence for EphA4 expression in corticospinal tract neurons themselves. First, X-gal staining was observed in layer 5 of the motor cortex, as well in as other layers. Second, corticospinal tract axons exhibited PLAP staining along their length, including in the internal capsule, at the pyramidal decussation, and in the spinal cord, where the pattern was consistent with expression in corticospinal tract axons and their collateral branches. In homozygotes, PLAP staining revealed an abnormal projection in the dorsal midline at the pyramidal decussation, suggesting crossing defects of corticospinal tract axons. Leighton et al. (2001) concluded that EphA4 may indeed act as a receptor in the corticospinal tract, a model further supported by the analysis of EphA4-kinase-deficient mice.
Kullander et al. (2001) generated mice expressing mutant EphA4 receptors either lacking kinase activity or with severely downregulated kinase activity. Kullander et al. (2001) demonstrated that EphA4 is required for corticospinal tract formation as a receptor, for which it requires an active kinase domain. In contrast, the formation of the anterior commissure is rescued by kinase-dead EphA4, suggesting that in this structure EphA4 acts as a ligand, for which its kinase activity is not required. Unexpectedly, the cytoplasmic sterile-alpha motif domain is not required for EphA4 functions.
Cowan, C. A., Yokoyama, N., Bianchi, L. M., Henkemeyer, M., Fritzsch, B. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 26: 417-430, 2000. [PubMed: 10839360] [Full Text: https://doi.org/10.1016/s0896-6273(00)81174-5]
Dottori, M., Hartley, L., Galea, M., Paxinos, G., Polizzotto, M., Kilpatrick, T., Bartlett, P. F., Murphy, M., Kontgen, F., Boyd, A. W. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Nat. Acad. Sci. 95: 13248-13253, 1998. [PubMed: 9789074] [Full Text: https://doi.org/10.1073/pnas.95.22.13248]
Fox, G. M., Holst, P. L., Chute, H. T., Lindberg, R. A., Janssen, A. M., Basu, R., Welcher, A. A. cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases. Oncogene 10: 897-905, 1995. [PubMed: 7898931]
Gallarda, B. W., Bonanomi, D., Mueller, D., Brown, A., Alaynick, W. A., Andrews S. E., Lemke, G., Pfaff, S. L., Marquardt, T. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320: 233-236, 2008. [PubMed: 18403711] [Full Text: https://doi.org/10.1126/science.1153758]
Gilardi-Hebenstreit, P., Nieto, M. A., Frain, M., Mattei, M. G., Chestier, A., Wilkinson, D. G., Charnay, P. An Eph-related receptor protein tyrosine kinase gene segmentally expressed in the developing mouse hindbrain. Oncogene 7: 2499-2506, 1992. Note: Erratum: Oncogene 8: 1103 only, 1993. [PubMed: 1281307]
Kullander, K., Butt, S. J. B., Lebret, J. M., Lundfald, L., Restrepo, C. E., Rydstrom, A., Klein, R., Kiehn, O. Role of EphA4 and ephrinB3 in local neuronal circuits that control walking. Science 299: 1889-1892, 2003. [PubMed: 12649481] [Full Text: https://doi.org/10.1126/science.1079641]
Kullander, K., Mather, N. K., Diella, F., Dottori, M., Boyd, A. W., Klein, R. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29: 73-84, 2001. [PubMed: 11182082] [Full Text: https://doi.org/10.1016/s0896-6273(01)00181-7]
Lai, C., Lemke, G. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron 6: 691-704, 1991. [PubMed: 2025425] [Full Text: https://doi.org/10.1016/0896-6273(91)90167-x]
Leighton, P. A., Mitchell, K. J., Goodrich, L. V., Lu, X., Pinson, K., Scherz, P., Skarnes, W. C., Tessier-Lavigne, M. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410: 174-179, 2001. [PubMed: 11242070] [Full Text: https://doi.org/10.1038/35065539]
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]
Sajjadi, F. G., Pasquale, E. B. Five novel avian Eph-related tyrosine kinases are differentially expressed. Oncogene 8: 1807-1813, 1993. [PubMed: 8510926]
Shi, L., Fu, W.-Y., Hung, K.-W., Porchetta, C., Hall, C., Fu, A. K. Y., Ip, N. Y. Alpha-2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc. Nat. Acad. Sci. 104: 16347-16352, 2007. [PubMed: 17911252] [Full Text: https://doi.org/10.1073/pnas.0706626104]