Alternative titles; symbols
HGNC Approved Gene Symbol: EPHA7
Cytogenetic location: 6q16.1 Genomic coordinates (GRCh38): 6:93,240,020-93,419,559 (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 biological 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 new members of the EPH/ELK family in human fetal brain. They identified 3 novel genes: HEK7 (EPHA5; 600004), HEK8 (EPHA4; 602188), and HEK11. HEK11 encodes a 998-amino acid polypeptide. Northern blotting of human tissues revealed that HEK11 is widely expressed with multiple transcript sizes.
Hartz (2014) mapped the EPHA7 gene to chromosome 6q16.1 based on an alignment of the EPHA7 sequence (GenBank BC027940) with the genomic sequence (GRCh37).
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 (601535)-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 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.
Depaepe et al. (2005) showed that ephrin-A/EphA receptor signaling plays a key role in controlling the size of the mouse cerebral cortex by regulating cortical progenitor cell apoptosis. In vivo gain of EphA receptor function, achieved through ectopic expression of ephrin-A5 in early cortical progenitors expressing EphA7, caused a transient wave of neural progenitor cell apoptosis, resulting in premature depletion of progenitors and a subsequent dramatic decrease in cortical size. In vitro treatment with soluble ephrin-A ligands similarly induced the rapid death of cultured dissociated cortical progenitors in a caspase-3 (CASP3; 600636)-dependent manner, thereby confirming a direct effect of ephrin/Eph signaling on apoptotic cascades. Conversely, in vivo loss of EphA function, achieved through EphA7 gene disruption, caused a reduction in apoptosis occurring normally in forebrain neural progenitors, resulting in an increase in cortical size and, in extreme cases, exencephalic forebrain overgrowth. Depaepe et al. (2005) concluded that these results identified ephrin/Eph signaling as a physiologic trigger for apoptosis that can alter brain size and shape by regulating the number of neural progenitors.
Salsi and Zappavigna (2006) reported that expression of Epha7 correlated with expression of Hoxa13 (142959) and Hoxd13 (142989) in developing mouse limb. They identified multiple putative Hox13-binding sites in the Epha7 promoter region and found that Hoxa13 and Hoxd13 bound 1 of these sites in vivo and that Hoxd13 bound this site in vivo in developing mouse limb. HOXD13 with a mutation in the homeodomain (I314L; 142989.0004), which causes a brachydactyly-polydactyly syndrome (see 113200), failed to bind and activate the EPHA7 promoter.
Depaepe, V., Suarez-Gonzalez, N., Dufour, A., Passante, L., Gorski, J. A., Jones, K. R., Ledent, C., Vanderhaeghen, P. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435: 1244-1250, 2005. [PubMed: 15902206] [Full Text: https://doi.org/10.1038/nature03651]
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]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/16/2014.
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]
Salsi, V., Zappavigna, V. Hoxd13 and Hoxa13 directly control the expression of the EphA7 ephrin tyrosine kinase receptor in developing limbs. J. Biol. Chem. 281: 1992-1999, 2006. [PubMed: 16314414] [Full Text: https://doi.org/10.1074/jbc.M510900200]