16 results on '"Gu, Changkyu"'
Search Results
2. The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease.
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Zhu, Ke, Mukherjee, Kamalika, Wei, Changli, Hayek, Salim S., Collins, Agnieszka, Gu, Changkyu, Corapi, Kristin, Altintas, Mehmet M., Wang, Yong, Waikar, Sushrut S., Bianco, Antonio C., Koch, Alexander, Tacke, Frank, Reiser, Jochen, and Sever, Sanja
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DISEASE risk factors ,TYPE 1 diabetes ,ETIOLOGY of diabetes ,CREATININE ,KIDNEY diseases ,MUSCULAR hypertrophy ,PANCREATIC enzymes ,PLASMINOGEN activators - Abstract
Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored β cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired β cell proliferation and inhibited the bioenergetics of β cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus. Editor's summary: Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for chronic kidney disease (CKD) progression. However, proteolysis of uPAR can also lead to generation of D2D3 protein. Here, Zhu and colleagues found that in serum samples from patients with diabetic nephropathy, D2D3 protein was predominantly associated with type 1 diabetes. They then generated D2D3 transgenic mice that developed kidney injury, insulin insufficiency, and diabetes associated with β cell injury on a high-fat diet, which could be improved by treatment with an anti-suPAR antibody. These findings highlight a role for D2D3 protein in the development of both kidney disease and diabetes and suggest that interventions targeting this protein could potentially improve both conditions. —Melissa Norton [ABSTRACT FROM AUTHOR]
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- 2023
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3. Dynamin Autonomously Regulates Podocyte Focal Adhesion Maturation
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Gu, Changkyu, Lee, Ha Won, Garborcauskas, Garrett, Reiser, Jochen, Gupta, Vineet, and Sever, Sanja
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- 2017
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4. Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models
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Schiffer, Mario, Teng, Beina, Gu, Changkyu, Shchedrina, Valentina A., Kasaikina, Marina, Pham, Vincent A., Hanke, Nils, Rong, Song, Gueler, Faikah, Schroder, Patricia, Tossidou, Irini, Park, Joon-Keun, Staggs, Lynne, Haller, Hermann, Erschow, Sergej, Hilfiker-Kleiner, Denise, Wei, Changli, Chen, Chuang, Tardi, Nicholas, Hakroush, Samy, Selig, Martin K., Vasilyev, Aleksandr, Merscher, Sandra, Reiser, Jochen, and Sever, Sanja
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Chronic kidney failure -- Models -- Causes of -- Development and progression -- Genetic aspects -- Research ,Actin -- Models -- Physiological aspects -- Genetic aspects -- Research ,Biological sciences ,Health - Abstract
Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to cross-link actin microfilaments into higher-order structures has been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the substantial regenerative potential of injured glomeruli and identifying the oligomerization cycle of dynamin as an attractive potential therapeutic target to treat CKD., Chronic kidney disease (CKD) affects hundreds of millions of people worldwide (1,2). It is associated with the appearance of significant amounts of high-molecular-weight plasma proteins in the urine (that is, [...]
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- 2015
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5. CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
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Yaddanapudi, Suma, Altintas, Mehmet M., Kistler, Andreas D., Fernandez, Isabel, Moller, Clemens C., Wei, Changli, Peev, Vasil, Flesche, Jan B., Forst, Anna-Lena, Li, Jing, Patrakka, Jaakko, Xiao, Zhijie, Grahammer, Florian, Schiffer, Mario, Lohmuller, Tobias, Reinheckel, Thomas, Gu, Changkyu, Huber, Tobias B., Ju, Wenjun, Bitzer, Markus, Rastaldi, Maria P., Ruiz, Phillip, Tryggvason, Karl, Shaw, Andrey S., Faul, Christian, Sever, Sanja, and Reiser, Jochen
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Transforming growth factors -- Physiological aspects -- Research ,Epithelial cells -- Physiological aspects -- Research ,Kidney diseases -- Development and progression -- Research ,Health care industry - Abstract
Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1-dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actinassociated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease., Introduction Several hundred million people worldwide-about 1 in 15 adults-have some form of kidney damage, and every year, millions die prematurely of cardiovascular or renal complications linked to chronic kidney [...]
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- 2011
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6. Regulation of Dynamin Oligomerization in Cells: The Role of Dynamin–Actin Interactions and Its GTPase Activity
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Gu, Changkyu, Chang, Joann, Shchedrina, Valentina A., Pham, Vincent A., Hartwig, John H., Suphamungmee, Worawit, Lehman, William, Hyman, Bradley T., Bacskai, Brian J., and Sever, Sanja
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- 2014
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7. Dynamin Rings: Not Just for Fission
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Sever, Sanja, Chang, Joann, and Gu, Changkyu
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- 2013
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8. The EphA8 receptor induces sustained MAP kinase activation to promote neurite outgrowth in neuronal cells
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Gu, Changkyu, Shim, Sungbo, Shin, Jongdae, Kim, Jieun, Park, Jonghoon, Han, Kyuhyung, and Park, Soochul
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- 2005
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9. The p110γ PI-3 kinase is required for EphA8-stimulated cell migration
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Gu, Changkyu and Park, Soochul
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CYTOSKELETAL proteins , *FIBRONECTINS - Abstract
This study provides evidence that treatment with preclustered ephrin A5-Fc results in a substantial increase in the stability of the p110γ PI-3 kinase associated with EphA8, thereby enhancing PI-3 kinase activity and cell migration on a fibronectin substrate. In contrast, co-expression of a lipid kinase-inactive p110γ mutant together with EphA8 inhibits ligand-stimulated PI-3 kinase activity and cell migration on a fibronectin substrate, suggesting that the mutant has a dominant negative effect against the endogenous p110γ PI-3 kinase. Significantly, the tyrosine kinase activity of EphA8 is not important for either of these processes. Taken together, our results demonstrate that the stimulation of cell migration on a fibronectin substrate by the EphA8 receptor depends on the p110γ PI-3 kinase but is independent of a tyrosine kinase activity. [Copyright &y& Elsevier]
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- 2003
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10. Genomic Structure and Promoter Analysis of the Mouse EphA8 Receptor Tyrosine Kinase Gene.
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Jeong, Jaemin, Choi, Sunga, Gu, Changkyu, Lee, Hansoo, and Park, Soochul
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MICE ,PROTEIN-tyrosine kinases ,PROMOTERS (Genetics) ,GENE mapping - Abstract
The gene encoding the mouse EphA8 receptor tyrosine kinase has been isolated from a mouse genomic library, and its complete genomic structure has been determined. This gene spans approximately 28 kb and consists of 17 exons. This gene structure is similar to the structure of the chick EphB2(Cek5) gene, except for one intron present between the first two exons encoding the EphA8 kinase domain. This difference may reflect an evolutionary divergence of the catalytic domain between EphA and EphB subgroup receptors. The site for transcription initiation has been mapped to the 19th nucleotide upstream from the translation start codon ATG. A feature of this gene is an unmethylated CpG island spanning exon 1 and the flanking sequence. The putative promoter of the EphA8 gene lacks a TATA box and contains multiple copies of the sequence GGGCGG, the core sequence of the putative Sp1-binding site. The 3.5-kb upstream genomic region containing part of the first exon showed strong promoter activity in NG108-15 neuroblastoma cells but much less in 293T cells, suggesting that this fragment is sufficient for neural cell-directed promoter activity. By deleting the genomic region containing the five GC boxes, it was shown that the minimal promoter region is primarily comprised of five copies of the Sp1-binding site located upstream from the transcription initiation site. Finally, in situ RNA hybridization studies revealed a very specific pattern of EphA8 gene expression restricted to the rostral region of midbrain tectum during embryonic development. Isolation of a functional promoter for the EphA8 gene is a first step in understanding how expression of this gene is controlled at the molecular level. [ABSTRACT FROM AUTHOR]
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- 2000
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11. Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis.
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Lee, Haeryung, Noh, Hyuna, Mun, Jiyoung, Gu, Changkyu, Sever, Sanja, and Park, Soochul
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- 2016
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12. Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease.
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Kistler AD, Singh G, Altintas MM, Yu H, Fernandez IC, Gu C, Wilson C, Srivastava SK, Dietrich A, Walz K, Kerjaschki D, Ruiz P, Dryer S, Sever S, Dinda AK, Faul C, and Reiser J
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- Animals, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Enzyme Activation, Glomerulonephritis, Membranous metabolism, Glomerulonephritis, Membranous pathology, Glomerulosclerosis, Focal Segmental pathology, Humans, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Podocytes pathology, Proteinuria metabolism, TRPC Cation Channels genetics, TRPC6 Cation Channel, Complement System Proteins metabolism, Glomerulosclerosis, Focal Segmental metabolism, Podocytes metabolism, TRPC Cation Channels metabolism
- Abstract
Gain-of-function mutations in the calcium channel TRPC6 lead to autosomal dominant focal segmental glomerulosclerosis and podocyte expression of TRPC6 is increased in some acquired human glomerular diseases, particularly in membranous nephropathy. These observations led to the hypothesis that TRPC6 overactivation is deleterious to podocytes through pathological calcium signaling, both in genetic and acquired diseases. Here, we show that the effects of TRPC6 on podocyte function are context-dependent. Overexpression of TRPC6 alone did not directly affect podocyte morphology and cytoskeletal structure. Unexpectedly, however, overexpression of TRPC6 protected podocytes from complement-mediated injury, whereas genetic or pharmacological TRPC6 inactivation increased podocyte susceptibility to complement. Mechanistically, this effect was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation. Podocyte-specific TRPC6 transgenic mice showed stronger CaMKII activation, reduced podocyte foot process effacement and reduced levels of proteinuria during nephrotoxic serum nephritis, whereas TRPC6 null mice exhibited reduced CaMKII activation and higher levels of proteinuria compared with wild type littermates. Human membranous nephropathy biopsy samples showed podocyte staining for active CaMKII, which correlated with the degree of TRPC6 expression. Together, these data suggest a dual and context dependent role of TRPC6 in podocytes where acute activation protects from complement-mediated damage, but chronic overactivation leads to focal segmental glomerulosclerosis.
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- 2013
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13. Direct dynamin-actin interactions regulate the actin cytoskeleton.
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Gu C, Yaddanapudi S, Weins A, Osborn T, Reiser J, Pollak M, Hartwig J, and Sever S
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- Amino Acid Sequence, Animals, Cells, Cultured, Dynamins antagonists & inhibitors, Dynamins genetics, Endocytosis physiology, HeLa Cells, Humans, Mice, Molecular Sequence Data, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, Podocytes metabolism, Protein Binding, RNA, Small Interfering pharmacology, Rabbits, Sequence Homology, Amino Acid, Actin Cytoskeleton metabolism, Actins metabolism, Cytoskeleton metabolism, Dynamins metabolism, Gelsolin metabolism, Stress Fibers metabolism
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The large GTPase dynamin assembles into higher order structures that are thought to promote endocytosis. Dynamin also regulates the actin cytoskeleton through an unknown, GTPase-dependent mechanism. Here, we identify a highly conserved site in dynamin that binds directly to actin filaments and aligns them into bundles. Point mutations in the actin-binding domain cause aberrant membrane ruffling and defective actin stress fibre formation in cells. Short actin filaments promote dynamin assembly into higher order structures, which in turn efficiently release the actin-capping protein (CP) gelsolin from barbed actin ends in vitro, allowing for elongation of actin filaments. Together, our results support a model in which assembled dynamin, generated through interactions with short actin filaments, promotes actin polymerization via displacement of actin-CPs.
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- 2010
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14. Transient activation of the MAP kinase signaling pathway by the forward signaling of EphA4 in PC12 cells.
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Shin J, Gu C, Kim J, and Park S
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- Animals, Base Sequence, Blotting, Western, DNA Primers, Endocytosis, Immunoprecipitation, PC12 Cells, Rats, Reverse Transcriptase Polymerase Chain Reaction, MAP Kinase Signaling System, Receptor, EphA4 metabolism
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In the present study, we demonstrate that ephrin-A5 is able to induce a transient increase of MAP kinase activity in PC12 cells. However, the effects of ephrin-A5 on the MAP kinase signaling pathway are about three-fold less than that of EGF. In addition, we demonstrate that EphA4 is the only Eph member expressed in PC12 cells, and that tyrosine phosphorylation induced by ephrin-A5 treatment is consistent with the magnitude and longevity of MAP kinase activation. Experiments using the Ras dominant negative mutant N17Ras reveal that Ras plays a pivotal role in ephrin-A5-induced MAP kinase activation in PC12 cells. Importantly, we found that the EphA4 receptor is rapidly internalized by endocytosis upon engagement of ephrin-A5, leading to a subsequent reduction in the MAP kinase activation. Together, these data suggest a novel regulatory mechanism of differential Ras-MAP kinase signaling kinetics exhibited by the forward signaling of EphA4 in PC12 cells.
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- 2008
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15. Identification of phosphotyrosine binding domain-containing proteins as novel downstream targets of the EphA8 signaling function.
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Shin J, Gu C, Park E, and Park S
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- Animals, Brain drug effects, Brain metabolism, Cell Line, Cell Movement drug effects, Ephrin-A5 pharmacology, Fetus drug effects, Fetus metabolism, Gene Library, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Mice, Neurites drug effects, Neurites enzymology, Protein Binding drug effects, Protein Structure, Tertiary, Protein Transport drug effects, Two-Hybrid System Techniques, Carrier Proteins metabolism, Phosphotyrosine metabolism, Receptor, EphA8 metabolism, Signal Transduction drug effects
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Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-1b and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA-1b and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required for this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells. Taken together, our findings support a possible function for Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.
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- 2007
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16. Identification of an enhancer region in the mouse ephA8 locus directing expression to the anterior region of the dorsal mesencephalon.
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Koo J, Shim S, Gu C, Yoo O, and Park S
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- 5' Flanking Region genetics, Animals, Ligands, Mice, Mice, Transgenic, Receptors, Eph Family genetics, Receptors, Eph Family metabolism, Superior Colliculi embryology, Superior Colliculi physiology, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Developmental physiology, Mesencephalon embryology, Mesencephalon physiology, Receptor, EphA8 genetics
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Eph receptors and ephrins are dynamically expressed in a wide range of regions of the vertebrate during embryogenesis. The dorsal mesencephalon appears to be segmented into two broad regions demarcated by the mutually exclusive expression of EphA receptors and ephrinA ligands. It is of considerable interest to elucidate how these expression domains are established in the development of the mesencephalon. In this study, we used a transgenic approach to define the cis-acting DNA regulatory elements involved in the anterior mesencephalon-specific expression of the mouse ephA8 gene. Our analyses of the temporal and spatial expression patterns of various ephA8/lacZ gene fusions in transgenic mice revealed that the 10-kb genomic DNA 5' immediately upstream of the ephA8 coding sequence is capable of directing lacZ expression in an ephA8-specific manner. Further deletion analyses of the ephA8 genomic region led to the identification of a 1-kb enhancer region, which directs expression in the embryo to the anterior region of the developing midbrain. This ephA8-specific regulatory DNA sequences can now be used in biochemical analyses to identify proteins modulating the anterior differentiation of the optic tectum, and in functional analyses to direct the expression of other developmentally important genes to this region., (Copyright 2003 Wiley-Liss, Inc.)
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- 2003
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