Embryo brain kinase: a novel gene of the eph/elk receptor tyrosine kinase family

Ellis, Jonathan D.; Liu, Qiurong; Breitman, Martin L.; Jenkins, Nancy A.; Gilbert, Debra J.; Copeland, Neal G.; Tempest, Heidi; Warren, Simon; Muir, Elizabeth M.; Schilling, Heather; Fletcher, Fred A.; Ziegler, Steven F.; Rogers, J. H.

doi:10.1016/0925-4773(95)00411-s

Cited by 62 publications

(34 citation statements)

References 55 publications

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“…However, MDK1 and Elf-1 are expressed in adjacent areas in the developing hindbrain. Whereas MDK1 shows high expression in the rostral part (Ciossek et al, 1995;Ellis et al, 1995), Elf-1 transcripts are detected in the caudal region of the hindbrain (Cheng and Flanagan, 1994 and data not shown). Since the expression of a truncated Sek receptor tyrosine kinase disrupts the segmental restriction of gene expression during early rhombomere speci®cation, Sek has been suggested to be involved in the interactions that regulate the segmental identity or movement of cell leading to a sorting of cell with odd and even segmental identity (Xu et al, 1995).…”

Section: Discussionmentioning

confidence: 78%

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Identification of Elf-1 and B61 as high affinity ligands for the receptor tyrosine kinase MDK1

Ciossek

Ullrich

1997

Oncogene

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Mouse Developmental Kinase 1 (MDK1) is a receptor tyrosine kinase of the eck/eph subfamily expressed in a variety of tissues during early mouse embryogenesis. To obtain further insight into the function of MDK1, we determined identity and localisation of its physiological ligand(s). Staining whole embryos with fusion proteins between the extracellular domain of MDK1 and human secreted alkaline phosphatase revealed areas of high receptor binding in the caudal mesencephalon, the frontal neocortex and the limb buds. This staining was sensitive to treatment with phosphatidylinositol-speci®c phospholipase C. Using Scatchard analysis, high a nity binding of Elf-1 (1.7610 710 M) and B61 (2.2610 710 M) towards MDK1 could be demonstrated. However, the transmembrane ligand Lerk2 displayed no measurable a nity for MDK1. Elf-1 and B61 bind to the three full-length MDK1 isoforms with similar dissociation constants. Slightly lower a nities were observed for the two truncated receptors MDK1-T1 and MDK1-T2. The activation of MDK1 with Elf-1 or B61 leads to the rapid autophosphorylation of MDK1 as well as tyrosine phosphorylation of an unknown 62 kDa phosphoprotein in Rat1 cells. These ®ndings implicate MDK1 in patterning processes during early mouse embryogenesis and suggest MDK1 involvement in early organogenesis and midbrain development.

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Section: Discussionmentioning

confidence: 78%

“…In situ staining of whole mouse embryos MDK1 is expressed at high levels during mouse development (Ciossek et al, 1995;Ellis et al, 1995).…”

Section: Resultsmentioning

confidence: 99%

Identification of Elf-1 and B61 as high affinity ligands for the receptor tyrosine kinase MDK1

Ciossek

Ullrich

1997

Oncogene

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“…The repulsive axon guidance signal, a molecule closely related to Elf-1, repels the growth of retinal axons and is also expressed in an anteriorto-posterior gradient in the tectum. Repulsive axon guidance signal and Elf-1 are ligands for receptors in the eph family (18,22), the largest group of receptor tyrosine kinases (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The complementary pattern of receptor-ligand expression by preand postsynaptic neurons fulfills a longstanding prediction of the chemoaffinity hypothesis.…”

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confidence: 93%

Regulation of topographic projection in the brain: Elf-1 in the hippocamposeptal system.

Gao

Zhang²,

Yokoyama³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

145

130

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The hippocampus and septum play central roles in one of the most important spheres of brain function: learning and memory. Although their topographic connections have been known for two decades and topography may be critical for cognitive functions, the basis for hippocamposeptal topographic projection is unknown. We now report for the first time that Elf-1, a membrane-bound eph family ligand, is a candidate molecular tag for the genesis of the hippocamposeptal topographic projection. Elf-i is expressed in an increasing gradient from dorsal to ventral septum. Furthermore, Elf-i selectively allows growth of neurites from topographically appropriate lateral hippocampal neurons, while inhibiting neurite outgrowth by medial hippocampal neurons.Complementary to the expression of Elf-1, an eph family receptor, Bsk, is expressed in the hippocampus in a lateral to medial gradient, consistent with a function as a receptor for Elf-i. Further, Elf-1 specifically bound Bsk, eliciting tyrosine kinase activity. We conclude that the Elf-1/Bsk ligandreceptor pair exhibits traits of a chemoaffinity system for the organization of hippocamposeptal topographic projections.Topographic projection is a general feature of brain architecture, and appears to be critical for appropriate coding and processing of information (1). Nevertheless, little is known about the mechanisms that govern topographic organization. Among the many regions exhibiting topographic relations, the hippocampus and septum have been the focus of intense interest, since these structures play central roles in learning and memory (2-5). The hippocampus projects to the lateral septum and receives afferents from the medial septum (6-8). Moreover, hippocampal projections to the lateral septum are arranged in a precise order. Axons from the medial hippocampus project to the dorsal lateral septum, whereas axons from the lateral hippocampus project to the ventral lateral septum (6-8). Molecular mechanisms underlying these topographic projections are unknown.The development of topographic projections is thought to require both long-range signals to guide axons to the general target area and local cues to specify individual targets precisely for each axon terminal (9-11). Long-range signals are likely to be diffusible, such as netrins, which attract selected, distant growth cones, while repelling others (12)(13)(14)(15). In contrast, local guidance cues must match axon terminals and specific cellular targets, a requirement accommodated by matching fixed tags on afferents and corresponding targets. Complementarity of molecular tags on afferents and targets was first postulated by Sperry in his chemoaffinity hypothesis more than 50 years ago (16,17). Only recently have specific candidate molecules been identified (18)(19)(20)(21)(22). The eph family ligand and receptor, Elf-1 and Mek4, are expressed as complementary gradients in the tectum and retina, respectively (18). The repulsive axon guidance signal, a molecule closely related to Elf-1, repels the growth of retina...

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“…Previous studies have shown that Eph family proteins are expressed in peripheral and auditory pathways in chick (Cramer et al, 2000(Cramer et al, , 2002Bianchi and Gray, 2002;Person et al, 2004;Siddiqui and Cramer, 2005) and mice (Henkemeyer et al, 1994;Ellis et al, 1995;Rogers et al, 1999;Pickles et al, 2002). Moreover, functional studies have shown that Eph signaling influences axon outgrowth and guidance in the chick brainstem (Cramer et al, , 2006.…”

mentioning

confidence: 94%

Auditory brainstem neural activation patterns are altered in EphA4‐ and ephrin‐B2‐deficient mice

Miko

Nakamura

Henkemeyer

et al. 2007

J of Comparative Neurology

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Auditory processing requires proper formation of tonotopically ordered projections. We have evaluated the role of an Eph receptor tyrosine kinase and an ephrin ligand in the development of these frequency maps. We demonstrated expression of EphA4 and ephrin-B2 in auditory nuclei and found expression gradients along the frequency axis in neonates. We tested the roles of EphA4 and ephrin-B2 in development of auditory projections by evaluating whether mutations result in altered patterns of expression of the immediate early gene c-fos after exposure to pure tone stimuli. We evaluated two nuclei, the dorsal cochlear nucleus (DCN) and the medial nucleus of the trapezoid body (MNTB), which project in two distinct auditory pathways. The mean number of c-fos-positive neurons in EphA4(-/-) DCN after 8-kHz pure tone stimulation was 42% lower than in wild-type DCN. Along the dorsoventral, tonotopic axis of DCN, the mean position of c-fos-positive neurons was similar for mutant and wild-type mice, but the spread of these neurons along the tonotopic axis was 35% greater for ephrin-B2(lacZ/+) mice than for wild-type mice. We also examined these parameters in MNTB after exposure to 40-kHz pure tones. Both EphA4(-/-) and ephrin-B2(lacZ/+) mice had significantly fewer c-fos-positive cells than wild-type littermates. The labeled band of cells was narrower and laterally shifted in EphA4(-/-) mice compared with wild-type mice. These differences in cell number and distribution suggest that EphA4 and ephrin-B2 signaling influence auditory activation patterns.

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Embryo brain kinase: a novel gene of the eph/elk receptor tyrosine kinase family

Cited by 62 publications

References 55 publications

Identification of Elf-1 and B61 as high affinity ligands for the receptor tyrosine kinase MDK1

Identification of Elf-1 and B61 as high affinity ligands for the receptor tyrosine kinase MDK1

Regulation of topographic projection in the brain: Elf-1 in the hippocamposeptal system.

Auditory brainstem neural activation patterns are altered in EphA4‐ and ephrin‐B2‐deficient mice

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