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Genetic Pathways Regulating Glutamate Levels in Retinal Müller Cells

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Abstract

Müller cells serve many functions including the regulation of extracellular glutamate levels. The product of two genes, Slc1a3 [aka solute carrier family 1 (glial high affinity glutamate transporter), member 3] and Glul (aka glutamine synthetase) are the primary role players that transport glutamate into the Müller cell and convert it into glutamine. In this study, we sought to identify the genetic regulation of both genes. Given their tightly coupled biological functions, we predicted that they would be similarly regulated. Using an array of 75 recombinant inbred strains of mice, we determined that Slc1a3 and Glul are differentially regulated by distinct chromosomal regions. Interestingly, despite their independent regulation, gene ontology analysis of tightly correlated genes reveals that the enriched and statistically significant molecular function categories of both directed acyclic graphs have substantial overlap, indicating that the shared functions of correlates of Slc1a3 and Glul include production and usage of ATP.

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References

  1. Ehinger B, Ottersen OP, Storm-Mathisen J, Dowling JE (1988) Bipolar cells in the turtle retina are strongly immunoreactive for glutamate. Proc Natl Acad Sci 85:8321–8325

    Article  PubMed  CAS  Google Scholar 

  2. Marc RE, Liu W-LS, Kalloniatis M, Raiguel SF, Van Haesendonck E (1990) Patterns of glutamate immunoreactivity in the goldfish retina. J Neurosci 10:4006–4034

    PubMed  CAS  Google Scholar 

  3. Van Haesendonck E, Missotten L (1990) Glutamate-like immunoreactivity in the retina of a marine teleost, the dragonet. Neurosci Lett 111:281–286

    Article  PubMed  Google Scholar 

  4. Kalloniatis M, Fletcher EL (1993) Immunocytochemical localization of the amino acid neurotransmitters in the chicken retina. J Comp Neurol 336:174–193

    Article  PubMed  CAS  Google Scholar 

  5. Yang C-Y, Yazulla S (1994) Glutamate-, GABA-, and GAD-immunoreactivities co-localize in bipolar cells of tiger salamander retina. Vis Neurosci 11:1193–1203

    Article  PubMed  CAS  Google Scholar 

  6. Jojich L, Pourcho RG (1996) Glutamate immunoreactivity in the cat retina: a quantitative study. Vis Neurosci 13:117–133

    Article  PubMed  CAS  Google Scholar 

  7. Stryer L (1988) Biochemistry, 3rd edn. W.H. Freeman and Co, New York

    Google Scholar 

  8. Cajal SR (1892) The Structure of the retina (trans: S.A. Thorpe and M. Glickstein (Thomas, 1972, Springfield, IL)

  9. Reichenbach A et al (1993) What do retinal Müller (glial) cells do for their neuronal ‘small siblings’? J Chem Neuroanat 6:201–213

    Article  PubMed  CAS  Google Scholar 

  10. Kanai Y, Hediger MA (1992) Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360:467–471

    Article  PubMed  CAS  Google Scholar 

  11. Pines G et al (1992) Cloning and expression of a rat brain l-glutamate transporter. Nature 360:464–467

    Article  PubMed  CAS  Google Scholar 

  12. Fairman WA, Vandengerg RJ, Arriza JL, Kavanaugh MP, Amara SG (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375:599–603

    Article  PubMed  CAS  Google Scholar 

  13. Schultz K, Stell WK (1996) Immunocytochemical localization of the high-affinity glutamate transporter, EAAC1, in the retina of representative vertebrate species. Neurosci Lett 211:191–194

    Article  PubMed  CAS  Google Scholar 

  14. Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94:4155–4160

    Article  PubMed  CAS  Google Scholar 

  15. Kanai Y, Trotti D, Nussberger S, Hediger MA (1997) The high-affinity glutamate transporter family, structure, function, and physiological relevance. In: Reith MEA (ed) Neurotransmitter transporters: structure, function, and regulation. Totowa, NJ, Humana Press

    Google Scholar 

  16. Otori Y et al (1994) Marked increase in glutamate-aspartate transporter (GLAST/GluT-1) mRNA following transient retinal ischemia. Mol Brain Res 27:310–314

    Article  PubMed  CAS  Google Scholar 

  17. Derouiche A, Rauen T (1995) Coincidence of l-glutamate/l-aspartate transporter (GLAST) and glutamine synthetase (GS) immunoreactions in retinal glia: evidence for coupling of GLAST and GS in transmitter clearance. J Neurosci Res 42(1):131–143

    Article  PubMed  CAS  Google Scholar 

  18. Rauen T, Rothstein JF, Wassle H (1996) Differential expression of three glutamate transporter subtypes in the rat retina. Cell Tissue Res 286:325–336

    Article  PubMed  CAS  Google Scholar 

  19. Lehre KP, Davanger S, Danbolt NC (1997) Localization of the glutamate transporter protein GLAST in rat retina. Brain Res 744:129–137

    Article  PubMed  CAS  Google Scholar 

  20. Brew H, Attwell D (1987) Electrogenic glutamate uptake is a major current carrier in the membrane of axolotl retinal glial cells. Nature 327:707–709

    Article  PubMed  CAS  Google Scholar 

  21. Barbour B, Brew H, Attwell D (1988) Electrogenic glutamate uptake in glial cells is activated by intracellular potassium. Nature 335:433–435

    Article  PubMed  CAS  Google Scholar 

  22. Bouvier M, Szatkowski M, Amato A, Attwell D (1992) The glial cell glutamate uptake carrier countertransports pH-changing ions. Nature 360:471–474

    Article  PubMed  CAS  Google Scholar 

  23. Gegelashvili M, Rodriguez-Kern A, Sung L, Shimamoto K, Gegelashvili G (2007) Glutamate transporter GLAST/EAAT1 directs cell surface expressio of FXYD1/gamma subunit of Na, K ATPase in human fetal astrocytes. Neurochem Int 50:916–920

    Article  PubMed  CAS  Google Scholar 

  24. Hertz L (1979) Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino acid transmitters. Prog Neurobiol 13:277–323

    Article  PubMed  CAS  Google Scholar 

  25. Pow DV, Crook DK (1996) Direct immunocytochemical evidence for the transfer of glutamine from glial cells to neurons: use of specific antibodies directed against the d-stereoisomers of glutamate and glutamine. Neuroscience 70(1):295–302

    Article  PubMed  CAS  Google Scholar 

  26. Peirce JL, Lu L, Gu J, Silver LM, Williams RW (2004) A new set of BXD recombinant inbred lines from advanced intercross populations. BMC Genetics 5:7

    Article  PubMed  Google Scholar 

  27. Williams RW, Airey DC, Kulkarni A, Zhou G, Lu L (2001) Genetic dissection of the olfactory bulbs of mice: QTLs on four chromosomes modulate bulb size. Behav Genet 31(1):61–77

    Article  PubMed  CAS  Google Scholar 

  28. Geisert EE et al (2009) Gene expression in the mouse eye: an online resource for genetics using 103 strains of mice. Mol Vis 15:1730–1763

    PubMed  CAS  Google Scholar 

  29. Cambien F, Tiret L (2005) Atherosclerosis: from genetic polymorphisms to system genetics. Cardiovasc Toxicol 5:143–152

    Article  PubMed  CAS  Google Scholar 

  30. Irizarry RA et al (2003) Summaries of Affymetrix GeneChip probe level data. (Translated from eng). Nucleic Acids Res 31(4):e15 (in eng)

    Article  PubMed  Google Scholar 

  31. Chesler EJ et al (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function (Translated from eng). Nat Genet 37(3):233–242 (in eng)

    Article  PubMed  CAS  Google Scholar 

  32. Chang B et al (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15:1847–1857

    Article  PubMed  CAS  Google Scholar 

  33. Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138:963–971

    PubMed  CAS  Google Scholar 

  34. Zhang B, Schmoyer D, Kirov S, Snoddy J (2004) GOTree machine (GOTM): a web-based platform for interpreting sets of interesting genes using gene ontology hierarchies (Translated from eng). BMC Bioinformatics 5:16 (in eng)

    Article  PubMed  Google Scholar 

  35. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57(1):289–300

    Google Scholar 

  36. Alberts B et al (2002) Molecular Biology of the Cell, 4th edn. Garland Publishing, Inc, New York

    Google Scholar 

  37. Sanchez RA, Ferris JP, Orgel LE (1967) Studies in prebiotic synthesis. II. Synthesis of purine precursors and amino acids from aqueous hydrogen cyanide. J Mol Biol 30:223–253

    PubMed  CAS  Google Scholar 

  38. Sanchez RA, Ferris JP, Orgel LE (1968) Studies in prebiotic synthesis. IV. Conversion of 4-aminoimidazole-5-carbonitrile derivatives to purines. J Mol Biol 38:121–128

    Article  PubMed  CAS  Google Scholar 

  39. Ferris JP, Kuder JE, Catalano AW (1969) Photochemical reactions and the chemical evolution of purines and nicotinamide derivatives. Science 166:765–766

    Article  PubMed  CAS  Google Scholar 

  40. Tsuda Y, Stephani RA, Meister A (1971) Formation of an acyl phosphate by glutamine synthetase. Biochemistry 10:3186–3189

    Article  PubMed  CAS  Google Scholar 

  41. Liaw SH, Kuo I, Eisenberg D (1995) Discovery of the ammonium substrate site on glutamine synthetase, a third cation binding site. Protein Sci 4:2358–2365

    Article  PubMed  CAS  Google Scholar 

  42. Shimura H et al (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302–305

    Article  PubMed  CAS  Google Scholar 

  43. Ortega Z, Diaz-Hernandez M, Lucas JJ (2007) Is the ubiquitin-proteasome system impaired in Huntington’s disease? Cell Molec Life Sci 64:2245–2257

    Article  PubMed  CAS  Google Scholar 

  44. Haberle J et al (2005) Congenital glutamine deficiency with glutamine synthetase. New Eng J Med 353:1926–1933

    Article  PubMed  Google Scholar 

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Acknowledgments

NIH Grants EY021200, EY017814, AA014425, AA017590, DA021131; NEI Core Grant P30EY013080; An Unrestricted Grant from Research to Prevent Blindness, New York, NY.

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Authors and Affiliations

  1. Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Science Center, 930 Madison Avenue, Suite 731, Memphis, TN, 38163, USA

    Monica M. Jablonski, Natalie E. Freeman, William E. Orr, Justin P. Templeton & Eldon E. Geisert

  2. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA

    Lu Lu & Robert W. Williams

Authors
  1. Monica M. Jablonski
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  2. Natalie E. Freeman
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  3. William E. Orr
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  4. Justin P. Templeton
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  5. Lu Lu
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  7. Eldon E. Geisert
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Correspondence to Monica M. Jablonski.

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Special Issue: In Honor of Dr. Dianna Johnson.

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Jablonski, M.M., Freeman, N.E., Orr, W.E. et al. Genetic Pathways Regulating Glutamate Levels in Retinal Müller Cells. Neurochem Res 36, 594–603 (2011). https://doi.org/10.1007/s11064-010-0277-1

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