Skip to main content
SpringerLink
Log in

Identification of transcriptionally regulated genes in response to cellular iron availability in rat hippocampus

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The present study was attempted to identify transcriptionally regulated genes of the normal neurocytes responsive to iron availability. Postnatal rat hippocampus cells were primarily cultured either under the iron-loaded or depleted conditions. These cultured cells were applied for the generation of subtracted complementary DNA libraries by the suppression subtraction hybridization (SSH) and for the subsequent identification of differentially expressed transcripts by reverse Northern blot. The differentially expressed genes were chosen to perform sequencing, and then some of them were performed by Northern blot analysis for observation of their expression in the hippocampus of rats with the different iron status. The results indicated that five unique transcripts were strong candidates for differential expression in cellular iron repletion, one of them is a novel sequence (Genbank No.AF433878), while 26 unique transcripts were strong candidates for differential expression in cellular iron deprivation, one of them is a novel sequence (Genbank No. AY 912101). The revealed known genes responsive to iron availability were previously unknown to respond to iron availability, or have not been determined in the brain, have not even been currently determined in their physiological and biological functions. Interestingly, the proteins encoded by most of the known genes are either directly pointed to or indirectly associated with the molecules that play important, even key roles in cellular signal transduction and the cell cycle. These findings lead to the important suggestion that the cellular responses to iron availability involve extensive transcriptional regulation and cellular signal transduction. Therefore, iron may serve as a signal, which directly and/or indirectly regulates or modulates cell functions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Lozoff B, Jimenez E, Wolf AW (1991) Long-term developmental outcome of infants with iron deficiency. N Engl J Med 325:687–694

    Article  PubMed  CAS  Google Scholar 

  2. Walter T, De Andraca I, Chadud P, Perales CG (1989) Iron deficiency anemia: adverse effects on infant psychomotor development. Pediatrics 84:7–17

    PubMed  CAS  Google Scholar 

  3. Pollit E (1989) Behavioral effects of iron deficiency in childhood. Am J Clin Nutr 50:666–667

    Google Scholar 

  4. Aukett MA, Parks YA, Scott PH, Wharton BA (1986) Treatment with iron increases weight gain and psychomotor development. Arch Dis Child 61:849–857

    Article  PubMed  CAS  Google Scholar 

  5. Beard J, Erikson KM, Jones BC (2003) Neonatal iron deficiency results in irreversible changes in dopamine function in rats. J Nutr 133:1174–1179

    PubMed  CAS  Google Scholar 

  6. Pinero D, Jones B, Beard J (2001) Variations in dietary iron alter behavior in developing rats. J Nutr 131:311–318

    PubMed  CAS  Google Scholar 

  7. Youdim MB (2000) Nutrient deprivation and brain function: iron. Nutrition 16:504–508

    Article  PubMed  CAS  Google Scholar 

  8. Xiao DS, Jiang L, Che LL, Lu L (2003) Nitric oxide and iron metabolism in exercised rat with L-arginine supplementation. Mol Cell Biochem 252:65–72

    Article  PubMed  CAS  Google Scholar 

  9. Xiao DS, Ho KP, Qian ZM (2004) Nitric oxide inhibition decreases bleomycin- detectable iron in spleen, bone marrow cells and heart but not in liver in exercise rats. Mol Cell Biochem 260:31–37

    Article  PubMed  CAS  Google Scholar 

  10. Levenson CW (2005) Trace metal regulation of neuronal apoptosis: from genes to behavior. Physiol Behav 86:399–406

    Article  PubMed  CAS  Google Scholar 

  11. Qian ZM, Shen X (2001) Brain iron transport and neurodegeneration. Trends Mol Med 7:103–108

    Article  PubMed  CAS  Google Scholar 

  12. Thomas M, Jankovic J (2004) Neurodegenerative disease and iron storage in the brain. Curr Opin Neurol 17:437–442

    Article  PubMed  Google Scholar 

  13. Beard JL, Wiesinger JA, Li N, Connor JR (2005) Brain iron uptake in hypotransferrinemic mice: influence of systemic iron status. J Neurosci Res 79:254–261

    Article  PubMed  CAS  Google Scholar 

  14. Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MB (2005) Gene expression profiling of sporadic Parkinson’s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKP1A, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci 1053:356–375

    Article  PubMed  CAS  Google Scholar 

  15. Bradbury MW (1997) Transport of iron in the blood–brain-cerebrospinal fluid system. J Neurochem 69:443–454

    Article  PubMed  CAS  Google Scholar 

  16. Burdo JR, Menzies SL, Simpson IA, Garrick LM, Garrick MD, Dolan KG, Haile DJ, Beard JL, Connor JR (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J Neurosci Res 66:1198–2207

    Article  PubMed  CAS  Google Scholar 

  17. Wu LJ, Leenders AG, Cooperman S, Meyron-Holtz E, Smith S, Land W, Tsai RY, Berger UV, Sheng ZH, Rouault TA (2004) Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res 1001:108–117

    Article  PubMed  CAS  Google Scholar 

  18. Pinero DJ, Li NQ, Connor JR, Beard JL (2000) Variations in dietary iron alter brain iron metabolism in developing rats. J Nutr 130:254–263

    PubMed  CAS  Google Scholar 

  19. Rao R, Tkac I, Townsend EL, Gruetter R, Georgieff MK (2003) Perinatal iron deficiency alters the neurochemical profile of the developing rat hippocampus. J Nutr 133:3215–3221

    PubMed  CAS  Google Scholar 

  20. Rao R, de Ungria M, Sullivan D, Wu P, Wobken JD, Nelson CA, Georgieff MK (1999) Perinatal brain iron deficiency increases the vulnerability of rat hippocampus to hypoxic ischemic insult. J Nutr 129:199–206

    PubMed  CAS  Google Scholar 

  21. Beard J (2003) Iron deficiency alters brain development and functioning. J Nutr 133:1468S–1472S

    PubMed  CAS  Google Scholar 

  22. Jorgenson LA, Wobken JD, Georgieff MK (2003) Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev Neurosci 25:412–420

    Article  PubMed  CAS  Google Scholar 

  23. Ye Z, Connor JR (2000) Identification of iron responsive genes by screening cDNA libraries from suppression subtractive hybridization with antisense probes from three iron conditions. Nucleic Acids Res 28:1802–1807

    Article  PubMed  CAS  Google Scholar 

  24. Liu Y, Popovich Z, Templeton DM (2005) Global genomic approaches to the iron-regulated proteome. Ann Clin Lab Sci 35:230–239

    PubMed  CAS  Google Scholar 

  25. Moos T, Morgan EH (1998) Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. J Neurosci Res 54:486–494

    Article  PubMed  CAS  Google Scholar 

  26. Ye Z, Connor JR (1999) Screening of transcriptionally regulated genes following iron chelation in human astrocytoma cells. Biochem Biophys Res Commun 264:709–713

    Article  PubMed  CAS  Google Scholar 

  27. Chua ACG, Olynyk JK, Leedman PJ, Trinder D (2004) Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Blood 104:1519–1525

    Article  PubMed  CAS  Google Scholar 

  28. Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol 2:406–414

    Article  PubMed  CAS  Google Scholar 

  29. Ho KP, Xiao DS, Ke Y, Qian ZM (2001) Exercise decreases cytosolic aconitase activity in the liver, spleen, and bone marrow in rats. Biochem Biophys Res Commun 282:264–267

    Article  PubMed  CAS  Google Scholar 

  30. Pantopoulos K (2004) Iron metabolism and the IRE/IRP regulatory system: an update. Ann N Y Acad Sci 1012:1–13

    Article  PubMed  CAS  Google Scholar 

  31. Sanchez M, Galy B, Dandekar T, Bengert P, Vainshtein Y, Stolte J, Muckenthaler MU, Hentze MW (2006) Iron regulation and the cell cycle: identification of an iron-responsive element in the 3’-untranslated region of human cell division cycle 14A mRNA by a refined microarray-based screening strategy. J Biol Chem 281:22865–22874

    Article  PubMed  CAS  Google Scholar 

  32. Chan LN, Gerhardt EM (1992) Transferrin receptor gene is hyperexpressed and transcriptionally regulated in differentiating erythroid cells. J Biol Chem 267:8254–8259

    PubMed  CAS  Google Scholar 

  33. Wilson SM, Bhattacharyya B, Rachel RA, Coppola V, Tessarollo L, Householder DB, Fletcher CF, Miller RJ, Copeland NG, Jenkins NA (2002) Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat Genet 32:420–425

    Article  PubMed  CAS  Google Scholar 

  34. Anderson C, Crimmins S, Wilson JA, Korbel GA, Ploegh HL, Wilson SM (2005) Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice. J Neurochem 95:724–731

    Article  PubMed  CAS  Google Scholar 

  35. Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278:40337–40342

    Article  PubMed  CAS  Google Scholar 

  36. Iwai K, Klausner RD, Rouault TA (1995) Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J 14:5350–5357

    PubMed  CAS  Google Scholar 

  37. Velasco G, Grkovic S, Ansieau S (2006) New insights into BS69 functions. J Biol Chem 281:16546–16550

    Article  PubMed  CAS  Google Scholar 

  38. Wan J, Zhang W, Wu L, Bai T, Zhang M, Lo KW, Chui YL, Cui Y, Tao Q, Yamamoto M, Akira S, Wu Z (2006) BS69, a specific adaptor in the latent membrane protein 1-mediated c-Jun N-terminal kinase pathway. Mol Cell Biol 26:448–456

    Article  PubMed  CAS  Google Scholar 

  39. Isobe T, Uchida C, Hattori T, Kitagawa K, Oda T, Kitagawa M (2006) Ubiquitin-dependent degradation of adenovirus E1A protein is inhibited by BS69. Biochem Biophys Res Commun 339:367–374

    Article  PubMed  CAS  Google Scholar 

  40. Yang YH, Zhao M, Li WM, Lu YY, Chen YY, Kang B, Lu YY (2006) Expression of programmed cell death 5 gene involves in regulation of apoptosis in gastric tumor cells. Apoptosis 11:993–1001

    Article  PubMed  CAS  Google Scholar 

  41. Cheng AX, Lou SQ, Zhou HW, Wang Y, Ma DL (2004) Expression of PDCD5, a novel apoptosis related protein, in human osteoarthritic cartilage. Acta Pharmacol Sin 25:685–690

    PubMed  CAS  Google Scholar 

  42. Bolte M, Steigemann P, Braus GH, Irniger S (2002) Inhibition of APC-mediated proteolysis by the meiosis-specific protein kinase Ime2. Proc Natl Acad Sci 99:4385–4390

    Article  PubMed  CAS  Google Scholar 

  43. Mizuno K, Tokumasu A, Nakamura A, Hayashi Y, Kojima Y, Kohri K, Noce T (2006) Genes associated with the formation of germ cells from embryonic stem cells in cultures containing different glucose concentrations. Mol Reprod Dev 73:437–445

    Article  PubMed  CAS  Google Scholar 

  44. Parfait B, Giovangrandi Y, Asheuer M, Laurendeau I, Olivi M, Vodovar N, Vidaud D, Vidaud M, Bieche I (2000) Human TIP49b/RUVBL2 gene: genomic structure, expression pattern, physical link to the human CGB/LHB gene cluster on chromosome 19q13.3. Ann Genet 43:69–74

    PubMed  CAS  Google Scholar 

  45. Nilsson J, Sengupta J, Frank J, Nissen P (2004) Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome. EMBO Rep 5:1137–1141

    Article  PubMed  CAS  Google Scholar 

  46. Snider MD (2003) A role for rab7 GTPase in growth factor-regulated cell nutrition and apoptosis. Mol Cell 12:796–797

    Article  PubMed  CAS  Google Scholar 

  47. Weimer JM, Custer AW, Benedict JW, Alexander NA, Kingsley E, Federoff HJ, Cooper JD, Pearce DA (2006) Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons. Neurobiol Dis 22:284–293

    Article  PubMed  Google Scholar 

  48. Schroer TA (2004) Dynactin. Annu Rev Cell Dev Biol 20:759–779

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was granted by: Project 30270639 supported by National Natural Science Foundation of China, BS2003022 supported by the Jiangsu Science and Techno1ogy Department, China, and 02JDG028 supported by the Doctoral Research Foundation of the Jiangsu University, China.

Author information

Authors and Affiliations

  1. Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, 226001, China

    Mei Liu

  2. Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, 212013, China

    De-Sheng Xiao

  3. Department of Applied Biology and Chemical Technology, Hongkong Polytechnic University, Hong Kong, China

    Zhong-Ming Qian

Authors
  1. Mei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. De-Sheng Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhong-Ming Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to De-Sheng Xiao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, M., Xiao, DS. & Qian, ZM. Identification of transcriptionally regulated genes in response to cellular iron availability in rat hippocampus. Mol Cell Biochem 300, 139–147 (2007). https://doi.org/10.1007/s11010-006-9377-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9377-2

Keywords

Search

Navigation