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At least 19 recordsLinked to original sources
PubMed1997

Diverse transcription factors are involved in the quantitative regulation of transcriptional activation of kappa promoters.

Immunoglobulin kappa promoters show sequence divergence but conserved function between different subgroups. Here we show that three separate 5' elements are required for synergistic stimulation of transcription with the decamer in a kappa promoter. These sites are a 5' E-box, a 3' AT-rich region in the pentadecamer (pd) element, and the kappa-Y element. Elf-1 is a novel kappa-Y element ligand induced upon mitogenic stimulation of resting B lymphocytes. Furthermore, the 5' E2A-like E-box in the pd element could be substituted by an upstream stimulatory factor motif with conservation of function. Thus, the synergistic activation requirements of kappa transcription is strictly dependent on the quantitative presence of transcription factor-binding motifs 5' of the decamer, but these differ qualitatively in that they may bind an array of proteins with conserved function.

Animals↗
PubMed1995

Ligands for EPH-related tyrosine kinase receptors are developmentally regulated in the CNS.

Elk is a member of the eph family of receptor-like tyrosine kinases. Although its function is unknown, elk is postulated to play a role in nervous system development. Using Northern analysis, we examined the developmental regulation of RNAs encoding elk, and several ligands for the eph family of RTKs, the LERKs. Expression of elk, LERK-1, and LERK-2 RNAs is high in all regions examined in the embryonic and postnatal rat brain and decreases to low levels with age. One exception is the adult olfactory bulb which continues to express a moderate level of LERK-2. In contrast, moderate LERK-4 expression was limited to the developing hippocampus and cerebral cortex. These data indicate that elk and some of the LERKs may play a role in nervous system development, maintenance, and/or regeneration.

Animals↗
PubMed1997

LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain.

The eph family is the largest subfamily of receptor tyrosine kinases (RTKs). Members of this subfamily display specific expression in the developing and adult brain. Recently, cDNAs encoding membrane bound ligands for these receptors have been identified which we have termed LERKs (ligand for eph-related kinases). We report here the isolation of LERK-7 from a human fetal brain cDNA library. LERK-7 encodes a protein of 228 amino acids and is anchored to the membrane by glycosyl-phosphatidylinositol (GPI) linkage. When transfected into CV1/EBNA cells, LERK-7 binds soluble forms of both hek and elk. In addition, a soluble form of LERK-7 will induce phosphorylation of eck expressed in a human duodenum adenocarcinoma cell line. LERK-7 expressed multiple transcripts (7.5-kb, 6.0-kb, and 3.5-kb) with the highest levels in human adult brain, heart, spleen, and ovary and human fetal brain, lung, and kidney. Similar to the other ligands in this family, LERK-7 is developmentally regulated in the brain. LERK-7 is identical to the recently described AL-1.

Adult↗
PubMed1996

Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina.

The Eph family of receptor tyrosine kinases and their ligands can be divided into two specificity subclasses: the Eck-related receptors and their GPI-anchored ligands, and the Elk-related receptors and their transmembrane ligands. Previous reports demonstrated that Eck- and Elk-related receptors in the retina distribute in high temporal-low nasal and high ventral-low dorsal gradients, respectively. While others have focused on complementary ligand gradients in the retinal axon target, the tectum, we report that ligands from each subclass also distribute in gradients opposing those of their corresponding receptors within the retina itself. Moreover, ligand gradients in the retina precede ganglion cell genesis. These results support an intraretinal role for Eph family members in addition to their previously proposed role in the development of retinotectal topography. The distinct distributions of Eph family members suggest that each subclass specifies positional information along independent retinal axes.

Animals↗
PubMed1996

The Eph kinase ligand AL-1 is expressed by rostral muscles and inhibits outgrowth from caudal neurons.

In the peripheral nervous system, neurons derived from specific rostrocaudal levels of the neuraxis selectively synapse on targets that arise from corresponding body positions. To identify molecules involved in such position-dependent connectivity, we used subtractive hybridization to isolate genes selectively expressed in rostral or caudal skeletal muscle. One mRNA that was more abundant in neck than in hindlimb muscles encoded the mouse ortholog of human AL-1 and chick RAGS, membrane-associated ligands of Eph tyrosine kinases that have recently been implicated in cortical axon fasciculation and retinotectal connectivity, respectively. We show here that mouse AL-1 is expressed in discrete regions of the central and peripheral nervous systems and in a subset of developing skeletal muscles. The abundance of AL-1 RNA in immortalized myogenic cell lines derived from rostral muscles is higher than in caudally derived lines, suggesting that levels are heritably maintained. Growth of neurites from cultured sensory ganglia and spinal cords is specifically inhibited by cells expressing AL-1, suggesting that this molecule could serve to guide peripheral axons. The inhibitory effects of AL-1 are position dependent, such that axons derived from caudal (lumbar) ganglia are more affected than those derived from rostral (cervical) ganglia. Together, these results support the notion that Eph kinases and their ligands regulate topographically appropriate neural connectivity in the peripheral nervous system, as well as in the central nervous system.

Amino Acid Sequence↗
PubMed1997

Lerk2 (ephrin-B1) is a collapsing factor for a subset of cortical growth cones and acts by a mechanism different from AL-1 (ephrin-A5).

The transmembrane (TM) subfamily of Eph ligands and their receptors have been implicated in axon pathfinding and in pattern formation during embryogenesis. These functions are thought to involve repulsive interactions but this has not been demonstrated directly. In this study we used a growth cone collapse assay to determine if the TM ligands Lerk2 and HtkL have repellant guidance activity. We show that Lerk2, but not HtkL, is a collapsing factor for a subset of embryonic cortical neurons. Analysis of the effects of Lerk2 on both the morphology and the cytoskeleton of cortical neurons suggests a mechanism of action different from that of AL-1, a GPI-linked Eph ligand having similar repellant activity. Treatment with Lerk2 disrupts the organization of both the actin cytoskeleton and the microtubules and induces the formation of swellings in the center of the growth cone and along the axon. Measurement of the relative F-actin concentrations in the neurites and soma indicated that F-actin levels in the neurites decrease while those in the soma increase, with the net F-actin content of the neuron remaining unchanged. In contrast, we show that prolonged treatment with AL-1 leads to a net loss of F-actin, consistent with the hypothesis that AL-1 acts by perturbing actin polymerization. These results provide evidence that the ectodomain of Lerk2 functions as a repellant guidance cue and show that, despite overlapping specificities in vitro, the biological activities of related ligands are not necessarily overlapping. Further, TM and GPI-linked Eph ligands appear to exert repellant activity by different mechanisms, opening up the possibility that they may have different effects on growth cones in vivo.

Actins↗
PubMed1994

Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases.

Mek4 and Sek are tyrosine kinases with expression patterns in the mouse embryo that suggest important functions in early development. However, like all Eph family kinases, both were identified as orphan receptors without known ligands. We show that Mek4 and Sek soluble receptor-alkaline phosphatase fusion proteins can be used in a procedure termed RAP in situ to identify regions of ligand expression in the mouse embryo. Based on this spatial information, a cDNA expression library was prepared, and was screened with the fusion proteins to identify Eph ligand family-1 (ELF-1). In cell lines and embryos, ELF-1 is membrane bound by a phosphatidylinositol tail, a feature that may account for unique biological functions. Its sequence is homologous with B61, a ligand for the Eck kinase, defining a family of related ligands. The expression domains of ELF-1, Mek4 and Sek indicate potential roles in embryonic patterning.

Amino Acid Sequence↗
PubMed1995

In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases.

The results of previous in vitro experiments indicate that a glycosylphosphatidylinositol (GPI)-anchored protein may play an important role in the guidance of temporal retinal axons during the formation of the topographically ordered retinotectal projection. We have purified and cloned a GPI-anchored, 25 kDa glycoprotein that is a good candidate for a molecule involved in this process. During the time of innervation by retinal ganglion cells, this protein is gradedly expressed in the posterior part of the developing tectum. In two different in vitro assay systems, the recombinant protein induces growth cone collapse and repulsion of retinal ganglion cell axons. These phenomena are observed for axons of temporal as well as nasal origin, indicating that an additional activity may be necessary to confer the nasotemporal specificity observed in previous assays. We named the protein RAGS (for repulsive axon guidance signal). The sequence of RAGS shows significant homology to recently identified ligands for receptor tyrosine kinases of the Eph subfamily.

Amino Acid Sequence↗
PubMed1995

Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map.

Topographic maps with a defined spatial ordering of neuronal connections are a key feature of brain organization. Such maps are believed to develop in response to complementary position-specific labels in presynaptic and postsynaptic fields. However, the complementary labeling molecules are not known. In the well-studied visual map of retinal axons projecting to the tectum, the labels are hypothesized to be in gradients, without needing large numbers of cell-specific molecules. We recently cloned ELF-1 as a ligand for Eph family receptors. Here, RNA hybridization shows matching expression gradients for ELF-1 in the tectum and its receptor Mek4 in the retina. Binding activity detected with alkaline phosphatase fusions of ELF-1 and Mek4 also reveals gradients and provides direct evidence for molecular complementarity of gradients in reciprocal fields. ELF-1 and Mek4 may therefore play roles in retinotectal development and have properties predicted of topographic mapping labels.

Amino Acid Sequence↗
PubMed1996

Cloning and expression of the murine Elf-1 cDNA.

The Ets family of transcription factors has been implicated in the etiology of several types of cancer. We cloned and characterized the gene encoding the murine homologue of one Ets family member, Elf-1 (mElf-1), in order to gain insight into its cellular physiology. We examined mElf-1 mRNA expression in normal mouse tissues and in several murine and human cell lines. Expression of mElf-1, although highest in lymphocytes, was observed in a number of hematopoietic cell lineages, including the myeloid, macrophages and erythroid lineages, and was lowest in the murine fibroblast cell line, NIH3T3. Analysis of human and fetal tissue mRNAs confirmed that mElf-1 is expressed in a variety of cell lineages, principally in hematopoietic cells. Western blot analysis using antiserum generated to a synthetic C-terminal peptide of mElf-1, and extracts prepared from cell lines that expressed the mElf-1 mRNA identified multiple mElf-1 species that migrated near the 97-kDa molecular weight marker. Site selection analysis indicated that the binding site preferred by mElf-1 is very similar to that of the Drosophila melanogaster homologue, E74, and to that of Fli-1, another Ets family member. We conclude that the expression of mElf-1 is not restricted to the lymphoid lineage, and suggest that Elf-1 may regulate the transcription of a broad spectrum of genes.

Amino Acid Sequence↗
PubMed1995

Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation.

REK7 is an Eph-related tyrosine kinase receptor expressed exclusively in the nervous system, predominantly in hippocampus and cortex. A soluble REK7-IgG fusion protein, produced to analyze the biological role of REK7, prevents axon bundling in cocultures of cortical neurons with astrocytes, a model of late stage nervous system development and differentiation. Using REK7-IgG as an affinity reagent, we purified and cloned a novel REK7 ligand called AL-1, a GPI-linked protein homologous to other members of an emerging ligand family. Membrane attachment of AL-1 appears necessary for receptor activation, since REK7 on cortical neurons is efficiently activated by transfected cells expressing GPI-linked AL-1, but not by soluble AL-1. Consistent with this, soluble AL-1 blocks axon bundling. Our findings, together with the observation that both molecules are expressed in the brain, suggest a role in the formation of neuronal pathways, a crucial feature of nervous system development and regeneration.

Amino Acid Sequence↗
PubMed1996

Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo.

Topographic maps, which maintain the spatial order of neurons in the order of their axonal connections, are found throughout the nervous system. In the visual retinotectal projection, ELF-1, a ligand in the tectum, and its receptors in the retina show complementary gradients in expression and binding, indicating they may be positional labels for map development. Here we show that ELF-1 acts as a repellent axon guidance factor in vitro. In vivo, when the tectal ELF-1 pattern is modified by retroviral overexpression, retinal axons avoid ectopic ELF-1 patches and map to abnormally anterior positions. All these effects were seen on axons from temporal but not nasal retina, indicating that ELF-1 could determine nasal versus temporal retinotectal specificity, and providing a direct demonstration of a cell recognition molecule with topographically specific effects on neural map development.

Animals↗
PubMed1997

The inhibitory effect on neurite outgrowth of motoneurons exerted by the ligands ELF-1 and RAGS.

Eph-related receptor tyrosine kinases and ligands are expressed at high levels in the developing nervous system, giving rise to the proposal that they are involved in neuronal connection. Cek8 was found to be predominantly expressed on a subset of motoneurons innervating limb but not body muscles during motoneuron axonal growth. Here we show that the ligands RAGS and ELF-1 were expressed in limb buds and that they activated Cek8 when presented in membrane-bound or clustered forms of Fc chimeric proteins but not in unclustered soluble forms. When chick embryonic motoneurons enriched by panning were cultured on clustered forms of RAGS-Fc and ELF-1-Fc, the neutrite growth of motoneurons expressing Cek8 was inhibited. Our results show a relationship between receptor phosphorylation and neurite growth inhibition and suggest that Eph-related kinases and ligands have a regulatory effect on the axon growth of motoneurons during development.

Animals↗
PubMed1997

The Eph family in retinal axon guidance.

The continued functional characterization of Eph-related receptors and ligands has provided further information toward an understanding of the mechanisms controlling the retinotectal projection. Recent in vivo analyses have strengthened the idea that Engrailed defines the positional identity of the tectum along the anteroposterior axis, possibly by regulating the expression of Eph family members.

Animals↗