University of Washington Xia Lab

Welcome to the laboratory of Dr. Zhengui Xia

Neural Stem Cell Function and Regulation

Neural Stem Cell

One of our research interests is to elucidate signal transduction mechanisms that regulate the fate of neural stem cells, i.e. what makes a neural stem cell proliferate and differentiate into neurons or glia in the mammalian brain. We are interested in neural stem cell regulation both during embryonic development and in adult brain (adult neurogenesis). Specifically, recent studies in our lab suggest a novel role for the ERK5 MAP kinase in regulating both developmental and adult neurogenesis. Using a combination of molecular, cellular, and in vivo animal models (inducible, conditional knockout mice), we are investigating 1) mechanisms by which ERK5 regulate neurogenesis; 2) functional consequence ERK5-regulated developmental neurogenesis on animal behavior; 3) functional consequence ERK5-regulated adult neurogenesis on animal behavior including olfaction, learning and memory, stress and depression etc.

II. Parkinson’s disease models

Parkinson's

We are also interested in molecular mechanisms and signal transduction pathways that regulate dopamine neuron death in Parkinson's disease models. We utilize both in vitro and in vivo, including inducible and conditional knockout mice to address these issues. It is our hope that these mechanistic studies may ultimately lead to the development of pharmacological interventions and clinical strategies for treatment of Parkinson's disease. These studies may also provide insights concerning the relationships between environmental toxicants and the etiology of neurodegenerative disorders.

Publications

  1. Tota, M. R., Xia, Z., Storm, D. R., and Schimerlik, M. I. (1990): Reconstitution of Muscarinic Receptor Mediated Inhibition of Adenylyl Cyclase. Mol. Pharmacol. 37: 950-957.
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  2. Xia, Z., and Storm, D. R. (1990): A-Type ATP Binding Consensus Sequence is Critical for the Catalytic Activity of the Calmodulin Sensitive Adenylate Cyclase from Bacillus anthracis. J. Biol. Chem. 265: 6517-6520.
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  3. Xia, Z., Refsdal, C. D. R., Merchant, K. M., Dorsa, D. M., and Storm, D. R. (1991) Distinct Patterns for the Distribution of mRNA for the Calmodulin-Sensitive Adenylate Cyclase in Rat Brain: Expression in Areas Associated with Learning and Memory. Neuron 6: 431-443.
  4. Choi, E. J., Xia, Z. and Storm, D. R. (1992) Stimulation of the Type III Olfactory Adenylyl Cyclase by Calcium and Calmodulin. Biochemistry 31: 6492-6498.
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  5. Xia, Z., Choi, E. J., Wang, F., and Storm, D. R. (1992) The Type III Calcium/Calmodulin Sensitive Adenylyl Cyclase is not Specific to Olfactory Sensory Neurons.Neurosci. Letters 144: 169-173.
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  6. Xia, Z., Choi, E. J., Wang, F., Blazynski C., and Storm, D. R. (1993) The Type I Calmodulin Sensitive Adenylyl Cyclase Is Neural Specific. J. Neurochem. 60: 305-311.
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  7. Villacres, E. C., Xia, Z., Bookbinder, L. H., Edelhoff, S., Adler, D. A., Disteche, C. M., and Storm, D. R. (1993) Cloning, Chromosomal Mapping, and Expression of Human Fetal Brain Type I Adenylyl Cyclase. Genomics 16: 473-478.
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  8. Wu, Z., Thomas, S. A., Xia, Z., Villacres, E. C., Palmiter, R. D., and Storm, D. R. (1995) Deficient Spatial Memory and Altered LTP in Type I Adenylyl Cyclase Mutant Mice. Proc. Natl. Acad. Sci. USA 92:220-224.
  9. Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., Greenberg, M. E. (1995) Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis. Science (Research Article) 270:1326-1331.

    Note: article was recently selected as a highly cited paper in the field of Biology & Biochemistry by ISI Essential Science Indicators (ESI). According to the ISI Essential Science indicators Web product, this paper was ranked number 9 among Clinical Medicine papers published in the last decade, with 2,462 citations as of June 2004.
  10. Xia, Z., Dudek, H., Miranti, C. K., Greenberg, M. E. (1996) Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK Dependent Mechanism. J. Neuroscience 16(17): 5425-5436.
  11. Dickens, M., Rogers, J., Cavanagh, J., Raitano, A., Xia, Z., Halpern, J. R., Greenberg, M. E., Sawyers, C. L., Davis, R. J. (1997) A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 277: 693-696.
  12. Xing, J., Kornhauser, J. M., Xia, Z., Thiele, E. A., and Greenberg, M. E. (1998) Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol. Cell. Biol. 18(4): 1946-1955.
  13. Yue, T. L., J. Niá, A. M Romanic, J. L. Gu, P. Keller, C. Wang, S. Kumar, G. L.Yuá, T. K. HartÜ, X. Wang, Z. Xia, W. E. DeWolf Jr and G. Z. Feuerstein (1999) TL1, a Novel TNF-like Cytokine, Induces Apoptosis in Endothelial Cells: Involvement of Activation of Stress Protein Kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and Caspase-3 Like Protease . J. Biol. Chem. 274: 1479-1486, 1999
  14. Hetman, M., Kanning, K., Smith-Cavanaugh, J. E. and Xia, Z. (1999) Neuroprotection by Brain-Derived Neurotrophic Factor Is Mediated by Extracellular-Signal-Regulated Kinase and Phosphatidylinositol-3 Kinase. J. Biol. Chem. 274: 22569-22580.
  15. Hetman, M., Smith-Cavanaugh, J. E., Kimelman, D. and Xia, Z., (2000) Role of Glycogen Synthase Kinase-3b in Neuronal Apoptosis Induced by Trophic Withdrawal. J. Neurosci. 20(7): 2567-2574.
  16. Namgung, Uk. and Xia, Z.(2000) Arsenite-Induced Apoptosis in Cortical Neurons Is Mediated by c-Jun N-Terminal Protein Kinase 3 and p38 Mitogen-Activated Protein Kinase. J. Neurosci. 20(17): 6442-6451.
  17. Ghatan, S., Larner, S., Kinoshita, Y., Hetman, M., Patel, L., Xia, Z., Youle, R. J., Morrison, R. S. (2000) p38 Mitogen activated protein kinase mediates Bax translocation and caspase induction in nitric oxide-induced apoptosis in neurons. J. Cell Biol. 150(2): 335-347.
  18. Poser, S., Impey, K., Trinh, K., Xia, Z., and Storm, D. R. (2000) SRF-dependent gene expression is required for mitogen-induced proliferation through a PI3 kinase signal transduction cascade. EMBO J. 19(18): 4955-4966.
  19. Wong, Scott T., Kien Trinh, Jia Wei, Graeme Lowe, Anuj Gaggar, Zhengui Xia, Geoffrey H. Gold and Daniel R. Storm. (2000) Disruption of the Type III Adenylyl Cyclase Gene Leads to Peripheral and Behavioral Anosmia in Transgenic Mice. Neuron 27: 487-497.
  20. Cavanaugh, J. E., Ham, J., Hetman, M., Poser, S., Yan, C., and Xia, Z. (2001) Differential Regulation of Mitogen Activated Protein Kinases ERK1/2 and ERK5 by Neurotrophins, Neuronal Activity and cAMP in Neurons. J. Neurosci. 21(2): 434-443.
  21. Figueroa Masot, X. A., Hetman, M., Higgins, M., Kokot, N., Xia, Z.(2001) Differential Role of Bcl-2 Phosphorylation in Paclitaxel (Taxol)-Induced Apoptosis in Post-Mitotic Neurons and Proliferating HEK 293 Cells. J. Neurosci. 21(13): 4657-67.
  22. Namgung, Uk., and Xia, Z. (2001) Arsenic induces apoptosis in rat cerebellar neurons which requires activation of JNK 3 and p38 MAP kinases. Toxicol. Appl. Pharmacol. 174(2): 130-8.
  23. Chan, G. C. K., Lernmark, U., Xia, Z. and Storm D. R. (2001) DNA Elements of the Type I Adenylyl Cyclase Gene Locus Enhance Reporter Gene Expression in Neurons and Pinealocytes. Eur. J. Neurosci. 13 (11), 2054-2066.
  24. Mabuchi, T., Kitagawa, K., Kuwabara, K., Takasawa, K., Ohtsuki,T., Xia, Z., Storm, D., Yanagihara, T., Hori, M., Matsumoto, M. (2001) Phopshorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J. Neurosci. 21: 9204-13.
  25. Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, Greenberg ME. (2002) CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron 34: 221-233.
  26. Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA.(2002) p38 Mitogen-activated Protein Kinase Mediates Hypoxic Regulation of Mdm2 and p53 in Neurons. J. Biol. Chem. 277(25): 22909-14.
  27. Ghahremani MH, Keramaris E, Shree T, Xia Z, Davis RJ, Flavell R, Slack RS, Park DS. (2002). Interaction of the c-Jun/JNK pathway and cyclin-dependent kinases in death of embryonic cortical neurons evoked by DNA damage. J. Biol. Chem. 277(38): 35586-96.
  28. Hetman M, Hsuan SL, Habas A, Higgins MJ, Xia Z. (2002) ERK1/2 Antagonizes Glycogen Synthase Kinase-3beta -induced Apoptosis in Cortical Neurons. J. Biol. Chem. 277(51): 49577-49584.
  29. Xia, Z. and Storm, D. R. (2002) CaRF, a Neuronal Transcription Factor that CaREs. Neuron. 33: 315-316.
  30. Poser, S. , Impey, S., Xia, Z. and Storm, D. R. (2003) Brain-derived neurotrophic factor protection of cortical neurons from serum withdrawal-induced apoptosis is inhibited by cAMP. (2003) J. Neurosci. 23(11): 4420-7.
  31. Liu, L., Cavanaugh, J. E., Wang, Y., Sakagami, H., Mao, Z., and Xia, Z. (2003) ERK5 Activation of MEF2-Mediated Gene Expression Plays A Critical Role In BDNF-Promoted Survival of Developing But Not Mature Cortical Neurons. Proc. Natl. Acad. Sci. USA 100(14): 8532-8537.
  32. Uk Namgung, Dong-Hee Kim, Scok-Rhi Lim, Zhengui Xia, (2003) Blockade of calcium entry accelerates arsenite-mediated apoptosis in rat cerebellar granule cells. Molecules and Cells. 15:256
  33. Caughlan, A., Newhouse, K., Namgung, U. and Xia, Z. (2004) Chlorpyrifos Induces Apoptosis In Rat Cortical Neurons That Is Regulated By A Balance Between p38 And ERK/JNK MAP Kinases. Tox. Sci. 78(1): 125-34.
  34. Newhouse, Kathleen, Shih-Ling Hsuan, Sandra H. Chang, Beibei Cai, Yupeng Wang, and Zhengui Xia (2004). Rotenone-Induced Apoptosis Is Mediated By p38 And JNK MAP Kinases In Human Dopaminergic SH-SY5Y Cells. Tox. Sci. 79: 137-146.
  35. Chang, Sandra H., Steve Poser, and Zhengui Xia(2004). A Novel Role For Serum Response Factor In Neuronal Survival . J. Neurosci. 24 (9): 2277-85.
  36. Tang X, Wang X, Gong X, Tong M, Park D, Xia Z, Mao Z (2005). Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 25(19): 4823-34.
  37. Xia, Z. and Storm, D. R. (2005) The Role of Calmodulin as a Signal Integrator for Synaptic Plasticity. Nature Reviews Neuroscience. 6: 267-276.
  38. Liu L, Cundiff P, Abel G, Wang Y, Faigle F, Sakagami H, Xu M, Xia Z (2006). Extracellular signal-regulated kinase (ERK) 5 is necessary and sufficient to specify cortial neuronal fate. PNAS. 103(25): 9697-9702.
  39. Cai, Beibei, Esther B. E. Becker, Azad Bonni, Zhengui Xia (2006). p38 MAP Kinase Mediates Apoptosis Through Phosphorylation of BimEL At Ser65. J. Biol. Chem. 281: 25215-25222.
  40. Hsuan, Shih-Ling, Heather M. Klintworth, and Zhengui Xia. (2006) Basic Fibroblast Growth Factor Protects Dopaminergic Cells against Rotenone Toxicity through activation of the Extracellular-Signal-Regulated Kinase 1/2 and Phosphatidylinositol-3 Kinase. J. Neurosci. 26: 4481-91.
  41. Wang Yupeng, Bing Su, and Zhengui Xia. (2006) BDNF Activates ERK 5 In Cortical Neurons via a Rapl-MEKK2 Signaling Cascade. J. Biol. Chem. 281: 35965-35974.
  42. Klintworth, Heather, Kathleen Newhouse, Ting-ting Li, Roland Faigle, Won-Seok Choi, Zhengui Xia. (2007) Activation of c-Jun N-terminal Protein Kinase is a Common Mechanism Underlying Paraquat- and Rotenone-Induced Dopaminergic Neuron Cell Death. Tox. Sci. 97(1): 149-162.
  43. Wang Yupeng, Lidong Liu, Zhengui Xia. (2007) Brain-derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte-enhancer factor 2C through an ERK1/2-RSK2 signaling cascade. J Neurochem. 102(3): 957-66.
  44. Cude, Kelly, Hyunjung Choi, Yupeng Wang, Shih-Ling Hsuan, Honglai Zhang, Cun-Yu Wang, and Zhengui Xia. (2007) Activation of the ERK5-NFKB Pathway is Critical for G2/M Progression in the Cell Cycle.  J. Cell Biol.177(2): 253-64.

    Note: This paper is highlighted as one of the key papers appearing in that issue of the journal and is discussed in a section called In this Issue.
  45. Dirocco DP, Zhengui Xia. (2007) Alpha males win again. Nat. Neurosci. 10(8): 938-40.
  46. Cai, Beibei, and Zhengui Xia. (2008) p38 regulates Bim transcription through FOXO3a. Apoptosis. 13(6): 803-10.
  47. Faigle, Roland, Lidong Liu, Paige Cundiff, K. Funa, and Zhengui Xia. (2008) Opposing effects of retinoid signaling on astrogliogenesis in embryonic day 13 and 17 cortical progenitor cells. J. Neurochem. 106(4): 1681-98.
  48. Choi WS, Kruse SE, Palmiter RD, and Xia Z. (2008) Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat. PNAS. 105: 15136-41.
  49. Cundiff, Paige, Lidong Liu, Yupeng Wang, Junhui Zou, Yung-Wei Pan, Glen Abel, Xin Duan, Guo-li Ming,  Chris Englund, Robert Hevner, Zhengui Xia. (2009) ERK5 MAP Kinase Regulates Neurogenin1 During Cortical Neurogenesis. PLoS ONE.
  50. Klintworth Heather, Gwenn Garden, and Zhengui Xia. (2009) Rotenone and paraquat do not directly activate microglia or induce inflammatory cytokine release. Neuroscience Letters.462: 1-5.
  51. Wang Z, Li V, Chan GC, Phan T, Nudelman AS, Xia Z and Storm DR (2009) Adult Type 3 Adenylyl Cyclase Deficient Mice are Obese. (2009) PLoS ONE: 4: e6979. (PMCID: PMC2735775)
  52. Choi WS, Abel G, Klintworth H, Flavell R. and Xia Z. JNK3 Mediates Paraquat- and Rotenone-Induced Dopaminergic Neuron Death. (2010) J. Neuropathol. Exp. Neurol.: 69(5):511-20.
  53. Choi WS, Palmiter Rd, and Xia Z. Loss of mitochondrial complex I activity potentiates dopaminergic neuron death induced by microtubule dysfunction in Parkinson's disease model. (2011) J. Cell Biol. 192: (5): 873-882

    Note: This paper is highlighted as one of the key papers appearing in that issue of the journal and is discussed in the section called In Focus.
  54. Zou J, Pan YW, Wang Z, Chang SH, Wang WB, Wang X, Tournier C, Storm DR, and Xia Z  Targeted Deletion of ERK5 MAP Kinase in the Developing Nervous System Impairs Development of GABAergic Interneurons in the Main Olfactory Bulb and Behavioral Discrimination between Structurally Similar Odorants. (2012) J. Neurosci: 32(12):4118-32.
  55. Pan YW, Chan GCK, Kuo CT, Storm DR, and Xia Z. Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Specifically in Adult Neurogenic Regions Impairs Contextual Fear Memory Extinction and Remote Fear Memory. (2012) J. Neurosci: 32(19): 6444-55.
  56. Pan YW, Zou J, Wang W, Sakagami H, Garelick MG, Abel G, Kuo CT, Storm DR, Xia Z. Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis. J. Biol Chem. 2012 Jul 6: 287(28):23306-17. Epub 2012 May 29.
  57. Chen X, Xia Z, Storm DR. Stimulation of electro-olfactogram responses in the main olfactory epithelia by airflow depends on the type 3 adenylyl cyclase. J Neurosci. 2012 Nov 7:32(45): 15769-78.
  58. Pan YW, Kuo CT, Storm DR, Xia Z. Inducible and targeted deletion of the ERK5 MAP kinase in adult neurogenic regions impairs adult neurogenesis in the olfactory bulb and several forms of olfactory behavior. PLoS One. 2012: 7(11):e49622. Epub 2012 Nov 21.
  59. Wang W, Pan YW, Wietecha T, Zou J, Abel GM, Kuo CT, Xia Z. Extracellular signal-regulated kinase 5 (ERK5) mediates prolactin-stimulated adult neurogenesis in the subventricular zone and olfactory bulb. J Biol Chem. 2013 Jan 25;288(4):2623-31.
  60. Pan YW, Storm DR, Xia Z. The maintenance of established remote contextual fear memory requires ERK5 MAP kinase and ongoing adult neurogenesis in the hippocampus. PLoS One. 2012;7(11):e50455.
  61. Zou J, Storm DR, Xia Z. Conditional Deletion of ERK5 MAP Kinase in the Nervous System Impairs Pheromone Information Processing and Pheromone-Evoked Behaviors. PLoS One. 2013 Oct 9;8(10):e76901.
  62. Li T, Pan YW, Wang W, Abel G, Zou J, Xu L, Storm DR, Xia Z. Targeted deletion of the ERK5 MAP kinase impairs neuronal differentiation, migration, and survival during adult neurogenesis in the olfactory bulb. PLoS One. 2013 Apr 22;8(4):e61948. doi: 10.1371/journal.pone.0061948. Print 2013.
  63. Li T, Wang W, Pan YW, Xu L, Xia Z. A hydroxylated metabolite of flame-retardant PBDE-47 decreases the survival, proliferation, and neuronal differentiation of primary cultured adult neural stem cells and interferes with signaling of ERK5 MAP kinase and neurotrophin 3. Toxicol Sci. 2013 Jul;134(1):111-24. doi: 10.1093/toxsci/kft083. Epub 2013 Apr 5.

SELECTED PEER-REVIEWED REVIEWS AND METHODS ARTICLES

  1. Choi E. J., Xia, Z., Villacres, E. C., and Storm, D. R. (1993) The Regulatory Diversity of the Mammalian Adenylyl Cyclases. Cur. Opinions in Cell Biol. 5: 269-273.
  2. Villacres. E. C., Xia, Z., Choi, E. J., and Storm, D. R. (1993) Calmodulin Regulation of Mammalian Adenylyl Cyclases. Cur. Topics in Mol. Pharmacol. 1: 51-54.
  3. Xia, Z., Choi E. J., Blazynski, C., and Storm, D. R. (1995) Do the Calmodulin Stimulated Adenylyl Cyclases Play a Role in Neuroplasticity? Behav. and Brain Sci. 18 (3): 429-440.
  4. Xia, Z. and Storm, D. R. (1997) Calmodulin-regulated adenylyl cyclases and neuromodulation. Cur. Opin Neurobiol 7(3): 391-396.
  5. Hetman M, Xia Z (2000) Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta Neurobiol Exp 60: 531-545.
  6. Xia, Z. (2002) Adenylyl cyclases. Wiley Encyclopedia of Molecular Medicine. Edited by T. A. Creighton. 5: 79-82.
  7. Xia, Z. and Storm, D. R. (2002) CaRF, a Neuronal Transcription Factor that CaREs. Neuron. 33: 315-316.
  8. Xia Z, Storm DR. (2005) The role of calmodulin as a signal integrator for synaptic plasticity. Nat Rev Neurosci. 6(4): 267-76.
  9. Dirocco, DP and Xia, Z. (2007) Alpha males win again. Nat Neurosci. 10(8): 938-40.
  10. Choi WS, Klintworth HM, Xia Z. (2011) JNK3-mediated apoptotic cell death in primary dopaminergic neurons. Methods Mol Biol. 758: 279-92.
  11. Xia Z, Storm DR. (2012) Role of signal transduction crosstalk between adenylyl cyclase and MAP kinase in hippocampus-dependent memory. Learn Mem. Aug 16; 19(9): 369-74.
  12. Pan YW, Storm DR, Xia Z. Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: new insights from ERK5 MAP kinase. Neurobiol Learn Mem. 2013 Oct;105:81-92. doi: 10.1016/j.nlm.2013.07.011. Epub 2013 Jul 18.
  13. Choi WS, Kim HW, Xia Z. Preparation of primary cultured dopaminergic neurons from mouse brain. Methods Mol Biol. 2013;1018:61-9. doi: 10.1007/978-1-62703-444-9_6.
  14. Pan YW, Wang W, Xia Z. Assessment of adult neurogenesis in mice. Curr Protoc Toxicol. 2013 May;Chapter 12:Unit12.20. doi: 10.1002/0471140856.tx1220s56.

BOOKS

  1. Xia, Z. and Storm, D. R. (1996) The Mammalian Adenylyl Cyclases. R. G. Landes Co. Mol. Bio. Intelligence Unit.