Browse > Article

Microarray Analysis of Differentially Expressed Genes in the Brains of Tubby Mice  

Lee, Jeong-Ho (Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine)
Kim, Chul-Hoon (Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine)
Kim, Dong-Goo (Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine)
Ahn, Young-Soo (Department of Pharmacology, Brain Research Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.13, no.2, 2009 , pp. 91-97 More about this Journal
Abstract
The tubby mouse is characterized by progressive retinal and cochlear degeneration and late-onset obesity. These phenotypes are caused by a loss-of-function mutation in the tub gene and are shared with several human syndromes, suggesting the importance of tubby protein in central nervous system (CNS) functioning. Although evidence suggests that tubby may act as a transcription factor mediating G-protein coupled receptor (GPCR) signaling, any downstream gene regulated by tubby has yet to be identified. To explore potential target genes of tubby with region-specific transcription patterns in the brain, we performed a microarray analysis using the cerebral cortex and hypothalamus of tubby mice. We also validated the changes of gene expression level observed with the microarray analysis using real-time RT-PCR. We found that expression of erythroid differentiation factor 1 (Erdrl) and caspase 1 (Casp1) increased, while p21-activated kinase 1 (Pak1) and cholecystokinin 2 receptor (Cck2r) expression decreased in the cerebral cortex of tubby mice. In the hypothalamic region, Casp 1 was up-regulated and $\mu$-crystallin (CRYM) was down-regulated. Based on the reported functions of the differentially expressed genes, these individual or grouped genes may account for the phenotype of tubby mice. We discussed how altered expression of genes in tubby mice might be understood as the underlying mechanism behind tubby phenotypes.
Keywords
Tubby; Microarray; Gene expression; Cerebral cortex; Hypothalamus;
Citations & Related Records

Times Cited By Web Of Science : 0  (Related Records In Web of Science)
Times Cited By SCOPUS : 1
연도 인용수 순위
  • Reference
1 Cau J, Hall A. Cdc42 controls the polarity of the actin and microtubule cytoskeletons through two distinct signal transduction pathways. J Cell Sci 118: 2579−2587, 2005   DOI   PUBMED   ScienceOn
2 Chandra R, Liddle RA. Cholecystokinin. Curr Opin Endocrinol Diabetes Obes 14: 63−67, 2007   ScienceOn
3 Clerc P, Coll Constans MG, Lulka H, Broussaud S, Guigne C, Leung-Theung-Long S, Perrin C, Knauf C, Carpene C, Penicaud L, Seva C, Burcelin R, Valet P, Fourmy D, Dufresne M. Involvement of cholecystokinin 2 receptor in food intake regulation: hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice. Endocrinology 148: 1039−1049, 2007   DOI   PUBMED   ScienceOn
4 Dormer P, Spitzer E, Frankenberger M, Kremmer E. Erythroid differentiation regulator (EDR), a novel, highly conserved factor I. Induction of haemoglobin synthesis in erythroleukaemic cells. Cytokine 26: 231−242, 2004b   DOI   PUBMED   ScienceOn
5 Gaudreau P, Quirion R, St-Pierre S, Pert CB. Characterization and visualization of cholecystokinin receptors in rat brain using $ [3_H]$pentagastrin. Peptides 4: 755−762, 1983   DOI   PUBMED   ScienceOn
6 Guan XM, Yu H, Van der Ploeg LH. Evidence of altered hypothalamic pro-opiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Brain Res Mol Brain Res 59: 273−279, 1998   DOI   PUBMED   ScienceOn
7 Hill DR, Shaw TM, Woodruff GN. Species differences in the localization of 'peripheral' type cholecystokinin receptors in rodent brain. Neurosci Lett 79: 286−289, 1987a   DOI   PUBMED   ScienceOn
8 Ikeda A, Naggert JK, Nishina PM. Genetic modification of retinal degeneration in tubby mice. Exp Eye Res 74: 455−461, 2002   DOI   PUBMED   ScienceOn
9 Jacobs T, Causeret F, Nishimura YV, Terao M, Norman A, Hoshino M, Nikolic M. Localized activation of p21-activated kinase controls neuronal polarity and morphology. J Neurosci 27: 8604−8615, 2007   DOI   ScienceOn
10 Mackay IM, Arden KE, Nitsche A. Real-time PCR in virology. Nucleic Acids Res 30: 1292−1305, 2002   DOI   PUBMED   ScienceOn
11 Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10: 417−426, 2002   DOI   PUBMED   ScienceOn
12 Roberts MR, Srinivas M, Forrest D, Morreale de Escobar G, Reh TA. Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc Natl Acad Sci U S A 103: 6218−6223, 2006   DOI   ScienceOn
13 Segovia L, Horwitz J, Gasser R, Wistow G. Two roles for mu-crystallin: a lens structural protein in diurnal marsupials and a possible enzyme in mammalian retinas. Mol Vis 3: 9, 1997   PUBMED
14 Suzuki S, Mori J, Kobayashi M, Inagaki T, Inaba H, Komatsu A, Yamashita K, Takeda T, Miyamoto T, Ichikawa K, Hashizume K. Cell-specific expression of NADPH-dependent cytosolic 3,5,3'-triiodo-L-thyronine-binding protein (p38CTBP). Eur J Endocrinol 148: 259−268, 2003   DOI   ScienceOn
15 Kremer H, van Wijk E, Marker T, Wolfrum U, Roepman R. Usher syndrome: molecular links of pathogenesis, proteins and pathways. Hum Mol Genet 15 Spec No 2: R262−270, 2006   DOI   ScienceOn
16 Hill DR, Campbell NJ, Shaw TM, Woodruff GN. Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists. J Neurosci 7: 2967−2976, 1987b
17 Lee JH, Lee J, Seo GH, Kim CH, Ahn YS. Heparin inhibits NF-kappaB activation and increases cell death in cerebral endothelial cells after oxygen-glucose deprivation. J Mol Neurosci 32: 145−154, 2007   DOI   ScienceOn
18 Ohlemiller KK, Hughes RM, Mosinger-Ogilvie J, Speck JD, Grosof DH, Silverman MS. Cochlear and retinal degeneration in the tubby mouse. Neuroreport 6: 845−849, 1995   DOI   PUBMED   ScienceOn
19 Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L. Implication of tubby proteins as transcription factors by structure-based functional analysis. Science 286: 2119−2125, 1999   DOI   PUBMED
20 Friedlander R. Role of caspase 1 in neurologic disease. Arch Neurol 57: 1273−1276, 2000   DOI   PUBMED   ScienceOn
21 Oshima A, Suzuki S, Takumi Y, Hashizume K, Abe S, Usami S. CRYM mutations cause deafness through thyroid hormone binding properties in the fibrocytes of the cochlea. J Med Genet 43: e25, 2006   DOI   PUBMED
22 Perche O, Doly M, Ranchon-Cole I. Caspase-dependent apoptosis in light-induced retinal degeneration. Invest Ophthalmol Vis Sci 48: 2753−2759, 2007   DOI   PUBMED   ScienceOn
23 Crawley JN, Corwin RL. Biological actions of cholecystokinin. Peptides 15: 731−755, 1994   DOI   PUBMED   ScienceOn
24 Wong ML, Medrano JF. Real-time PCR for mRNA quantitation. Biotechniques 39: 75−85, 2005   DOI   PUBMED   ScienceOn
25 O'Shea E, Sanchez V, Orio L, Escobedo I, Green AR, Colado MI. 3,4-Methylenedioxymethamphetamine increases pro-interleukin- 1beta production and caspase-1 protease activity in frontal cortex, but not in hypothalamus, of Dark Agouti rats: role of interleukin-1beta in neurotoxicity. Neuroscience 135: 1095−1105, 2005   DOI   PUBMED   ScienceOn
26 Tang Y, Zhou H, Chen A, Pittman RN, Field J. The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem 275: 9106−9109, 2000   DOI   PUBMED   ScienceOn
27 Abe S, Katagiri T, Saito-Hisaminato A, Usami S, Inoue Y, Tsunoda T, Nakamura Y. Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues. Am J Hum Genet 72: 73−82, 2003   DOI   PUBMED   ScienceOn
28 Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 72: 743−781, 2003   DOI   PUBMED   ScienceOn
29 Umeda S, Suzuki MT, Okamoto H, Ono F, Mizota A, Terao K, Yoshikawa Y, Tanaka Y, Iwata T. Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J 19: 1683−1685, 2005   DOI
30 Katsanis N, Lupski JR, Beales PL. Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet 10: 2293−2299, 2001   DOI   PUBMED   ScienceOn
31 Morency MA, Quirion R, Mishra RK. Distribution of cholecystokinin receptors in the bovine brain: a quantitative autoradiographic study. Neuroscience 62: 307−316, 1994   DOI   PUBMED   ScienceOn
32 Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L. G-protein signaling through tubby proteins. Science 292: 2041−2050, 2001   DOI   PUBMED   ScienceOn
33 Schurmann A, Mooney AF, Sanders LC, Sells MA, Wang HG, Reed JC, Bokoch GM. p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol Cell Biol 20: 453−461, 2000   DOI   PUBMED   ScienceOn
34 Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol 7: 202−210, 1997   DOI   ScienceOn
35 Dormer P, Spitzer E, Moller W. EDR is a stress-related survival factor from stroma and other tissues acting on early haematopoietic progenitors (E-Mix). Cytokine 27: 47−57, 2004a   PUBMED   ScienceOn
36 Gillingwater TH, Wishart TM, Chen PE, Haley JE, Robertson K, MacDonald SH, Middleton S, Wawrowski K, Shipston MJ, Melmed S, Wyllie DJ, Skehel PA, Coleman MP, Ribchester RR. The neuroprotective WldS gene regulates expression of PTTG1 and erythroid differentiation regulator 1-like gene in mice and human cells. Hum Mol Genet 15: 625−635, 2006   DOI   PUBMED   ScienceOn
37 Ikeda S, He W, Ikeda A, Naggert JK, North MA, Nishina PM. Cell-specific expression of tubby gene family members (tub, Tulp1,2, and 3) in the retina. Invest Ophthalmol Vis Sci 40: 2706−2712, 1999   PUBMED
38 Zapala MA, Hovatta I, Ellison JA, Wodicka L, Del Rio JA, Tennant R, Tynan W, Broide RS, Helton R, Stoveken BS, Winrow C, Lockhart DJ, Reilly JF, Young WG, Bloom FE, Barlow C. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc Natl Acad Sci U S A 102: 10357−10362, 2005   DOI   ScienceOn
39 Schwartz MW, Porte D, Jr. Diabetes, obesity, and the brain. Science 307: 375−379, 2005   DOI   PUBMED   ScienceOn
40 Wang Y, Barbacioru C, Hyland F, Xiao W, Hunkapiller KL, Blake J, Chan F, Gonzalez C, Zhang L, Samaha RR. Large scale real-time PCR validation on gene expression measurements from two commercial long-oligonucleotide microarrays. BMC Genomics 7: 59, 2006   DOI   PUBMED   ScienceOn
41 Stubdal H, Lynch CA, Moriarty A, Fang Q, Chickering T, Deeds JD, Fairchild-Huntress V, Charlat O, Dunmore JH, Kleyn P, Huszar D, Kapeller R. Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol Cell Biol 20: 878−882, 2000   DOI   PUBMED   ScienceOn
42 Suzuki S, Mori J, Hashizume K. Mu-crystallin, a NADPH- dependent T(3)-binding protein in cytosol. Trends Endocrinol Metab 18: 286−289, 2007   DOI   ScienceOn
43 Orio L, O'Shea E, Sanchez V, Pradillo JM, Escobedo I, Camarero J, Moro MA, Green AR, Colado MI. 3,4-Methylenedioxymethamphetamine increases interleukin-1beta levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5-HT depletion. J Neurochem 89: 1445−1453, 2004   DOI   PUBMED   ScienceOn
44 Bode C, Wolfrum U. Caspase-3 inhibitor reduces apototic photoreceptor cell death during inherited retinal degeneration in tubby mice. Mol Vis 9: 144−150, 2003   PUBMED   ScienceOn
45 Hing H, Xiao J, Harden N, Lim L, Zipursky SL. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila. Cell 97: 853−863, 1999   DOI   PUBMED   ScienceOn
46 Koritschoner N, Alvarez-Dolado M, Kurz S, Heikenwalder M, Hacker C, Vogel F, Munoz A, Zenke M. Thyroid hormone regulates the obesity gene tub. EMBO Rep 2: 499−504, 2001   PUBMED   ScienceOn
47 Coleman DL, Eicher EM. Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered 81: 424−427, 1990   ScienceOn
48 Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, Wu Y, Berkemeier LR, Misumi DJ, Holmgren L, Charlat O, Woolf EA, Tayber O, Brody T, Shu P, Hawkins F, Kennedy B, Baldini L, Ebeling C, Alperin GD, Deeds J, Lakey ND, Culpepper J, Chen H, Glucks-mann-Kuis MA, Carlson GA, Duyk GM, Moore KJ. Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell 85: 281−290, 1996   DOI   PUBMED   ScienceOn