Zhengui Xia, PhD, MS

Professor, Env. and Occ. Health Sciences (Primary department)
Adjunct Professor, Pharmacology
I am a Professor in the Toxicology Program and an Adjunct Professor in the department of Pharmacology. I am also a Faculty member of the two interdisciplinary graduate programs at U. of Washington- the Neurobiology and Behavior (N&B) Graduate Program and the Molecular and Cell Biology (MCB) Graduate Program. We have two major research interests: 1) mechanisms that regulate apoptosis especially in relation to neurodegeneration (Parkinson’s disease) and toxin-induced neuronal damage; 2) mechanisms that regulate neurogenesis including neuronal fate determination, neuronal survival and differentiation both during brain development and in adult brain. Our lab is a medium sized lab that consists of post-doctoral fellows and students who are bright, motivated, collegial and friendly.

Contact Information

Box: 357234
1959 NE Pacific Street
Seattle, WA 98195-
Tel: 206-616-9433

Affiliations

  • Department of Pharmacology
  • Graduate Program in Neurobiology and Behavior
  • Graduate Program in Molecular and Cell Biology
  • Institute for Stem Cell and Regenerative Medicine (ISCRM)

Research Interests

  • Mechanisms for regulation of apoptosis in animal cells; Mechanisms of neurogenesis
  • KEYWORDS: Apoptosis, Neurogenesis, Adult neurogenesis, Children's health, Developmental toxicology, Genetic susceptibility to toxins, Nervous system toxicity, Parkinson's disease, Pesticides, Toxicology, Neurotoxicology, Neurobiology, Bioactivation/Carcinogenesis, Drug metabolism

Teaching interests

Toxicology, Carcinogenesis, Neuronal Signaling, Neurotoxicology, Research proposal preparation (grant writing)

Education

PhD, Pharmacology, University of Washington, 1991
MS, Biochemistry, Wuhan University (China), 1985

Projects

I. Neural Stem Cell Function and Regulation

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 extracellular-signal-regulated kinase 5 (ERK5) MAP kinase in regulating these processes. The elucidation of molecular mechanisms that regulate neural progenitor cell proliferation and differentiation is important for an understanding of neural developmental and neurodegenerative diseases. Furthermore, stem cell-based cell replacement therapy offers enormous potential for the treatment of a variety of developmental, psychiatric, neurodegenerative and aging related diseases for which there are currently no cures. Moreover, environmental toxicants may cause neurotoxicity both in the development and in adult brain by perturbing these signaling mechanisms that regulate neurogenesis.

II. Regulation of Neuronal Survival and Cell Death

Our laboratory is also interested in molecular mechanisms and signal transduction pathways that regulate neuronal survival and cell death. It has become increasingly evident that many environmental toxicants might contribute to the development of neurodegenerative disorders including Parkinson's disease. Our recent effort has focused on elucidating signaling mechanisms that regulate dopaminergic neuron cell death in relation to Parkinson's disease using exposure to several pesticides as model systems. 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.
Selected Publications

A. Refereed Research Articles

It is customary in Toxicology, Neurobiology and Signal Transduction Biology for students and postdoctoral fellows to be listed as the first author while the PI is indicated as the senior author by assuming the last position on journal publications. Those articles in which I am the senior author as PI are marked by  **.

  1. Xia, Z., Zhu, R., Cao, X., and Zou, G. (1987) Purification and characterization of restriction endonuclease Bsp 78I. Acta Biochim. Biophys. Sinica (Chinese). 19: 27-34.
  2. 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.
  3. 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.
  4. 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.
  5. Choi, E. J., Xia, Z. and Storm, D. R. (1992) Stimulation of the Type III Olfactory Adenylyl Cyclase by Calcium and Calmodulin.  Biochem.  31: 6492-6498.
  6. 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. Lett.  144: 169-173.
  7. 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.
  8. 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.
  9. 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.
  10. 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: Reference #10 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 at #9 among Clinical Medicine papers published in the past decade, with 2,462 citations as of June 2004. (http://www.incites.com/papers/DrZhenguiXia.html)
  11. 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. Neurosci. 16(17): 5425-5436.
  12. 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.
  13. 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.
  14. 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
  15. **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.
  16. **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.
  17. **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.
  18. 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.
  19. 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.
  20. Scott T. Wong, 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.
  21. **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.
  22. **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.
  23. **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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.    
  28. 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.
  29. **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.
  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. **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.
  32. **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. (PMCID: PMC166263)
  33. **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.
  34. **Kathleen Newhouse*, 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. **Sandra H. Chang, 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. Cyclin-dependent kinase 5 mediates neurotoxin-induced degradation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 2005: 25(19):4823-3.
  37. **Shih-Ling Hsuan, Heather M. Klintworth, and Zhengui Xia. (2006) Basic Fibroblast Growth Factor Protects Dopaminergic Cells against Rotenone Toxicity through activation of the Extracellular-Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase. J. Neurosci. 26:4481-91.
  38. **Lidong Liu , Paige Cundiff , Glen Abel , Yupeng Wang , Roland Faigle , Hiroyuki Sakagami, Mei Xu, Zhengui Xia (2006)  Extracellular Signal-Regulated Kinase (ERK) 5 Is Necessary and Sufficient to Specify Cortical Neuronal Fate. Proc. Natl. Acad. Sci. USA. 103(25):9697-702. Epub 2006 Jun 9. (PMCID: PMC1480469)
  39. **Beibei Cai,  Esther B. E. Becker, Azad Bonni, and Zhengui Xia. (2006) p38 MAP Kinase Mediates Apoptosis Through Phosphorylation of BimEL At Ser65. J. Biol. Chem. 281(35):25215-22. Epub 2006 Jul 3.
  40. **Yupeng Wang, Bing Su, and Zhengui Xia. (2006) BDNF Activates ERK5 In Cortical Neurons via a Rap1-MEKK2 Signaling Cascade J. Biol. Chem. 281 (47): 35965-74. Epub 2006 Sept 25. (PMID: 17003042)
  41. **Cude K, Wang Y, Choi HJ, Hsuan SL, Zhang HL, Wang CY, and Xia Z. (2007) Regulation of the G2/M Cell Cycle Progression by the ERK5-NFkB Signaling Pathway. J. Cell Biol. 177 (2): 253-64. (PMCID: PMC2064134)
  42. 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”.

  43. **Heather Klintworth, 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 Cell Death. Tox. Sci. 97(1): 149-62. (PMID: 17324951).
  44. **Yupeng Wang, Lidong Liu, and Zhengui Xia (2007). BDNF stimulates the transcriptional a (nd neuroprotective activity of myocyte-enhancer factor 2C through an ERK1/2-RSK2 signaling cascade. J. Neurochem. 102(3): 957-66. (PMID: 17630987)
  45. **Roland Faigle, Lidong Liu, Keiko Funa, and Zhengui Xia. (2008) Opposing effects of retinoid signaling on astroglial differentiation in progenitor cells derived from Embryonic day 13 and day 17 cortex. J. Neurochem. 106(4): 1681-98. (PMCID: PMC2581522)
  46. **Beibei Cai and Zhengui Xia. (2008) p38 MAP Kinase Mediates Arsenite-Induced Apoptosis through FOXO3a Activation and Induction of Bim Transcription. Apoptosis: 13:803–810. (PMCID: PMC2442769)
  47. **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 USA: 105: 15136-41. (PMCID: PMC2567505).
  48. **Cundiff P, Liu L, Wang Y, Zou J, Pan Y, Abel G, Duan X, Ming G, Englund C, Hevner R, Xia Z. (2009) ERK5 MAP Kinase Regulates Neurogenin1 During Cortical Neurogenesis. PLoS One: 4(4):e5204. Epub 2009 Apr 13. (PMCID: PMC2664926).
  49. **Klintworth H, Garden G, Xia Z.. Rotenone and Paraquat do not Directly Activate Microglia or Induce Inflammatory Cytokine Release. (2009) Neurosci. Lett: 462: 1-5 (PMCID: PMC2796146).
  50. 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).
  51. **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. (PMCID: PMC3061491)
  52. **Choi WS, Palmiter RD, and Xia Z. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model. (2011) J. Cell Biol. 192: (5): 873-882 (PMCID: PMC3051820 [PubMed - in process])
  53. 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 Focus”, by Ben Short,  The wrong suspect? (2011) J. Cell Biol. 192: (5): 707.

  54. **Zou J, Pan YW, Wang Z, Chang SH, Wang WB, Wang X, Tournier C,, Storm DR, and Xia Z  (2012) 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. J. Neurosci. 32 (12):4118-4132.
  55. **Pan YW, Zou J, Sakagami H, Garelick MG, Kuo CT, Storm DR, and Xia Z. ERK5 MAP Kinase is necessary and sufficient for regulating adult hippocampal neurogenesis (under revision at J. Biol. Chem).
  56. **Pan YW, Chan GCK, Kuo CT, Storm DR, and Xia Z. (2012) 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. J. Neurosci. (in press)
  57. **Wang WB, Pan YW, Xia, Z. ERK5 MAP kinase signals mating-induced adult neurogenesis (submitted)
  58. **Choi WS, Kim HW, Xia Z. Preparation of Primary Cultured Dopaminergic Neurons from Mouse Brain. Invited book chapter in “Methods in Molecular Biology”, Humana Press. (submitted)

B.  Refereed review articles

Choi E. J., Xia, Z., Villacres, E. C., and Storm, D. R. (1993) The Regulatory Diversity of the Mammalian  Adenylyl Cyclases. Cur.  Opin. Cell Biol. 5: 269-273.

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.

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.

Xia, Z. and Storm, D. R. (1997) Calmodulin-regulated adenylyl cyclases and neuromodulation. Cur. Opin. Neurobiol. 7(3):391-396.

** Xia, Z. (2002) Adenylyl cyclases. Wiley Encyclopedia of Molecular Medicine. Edited by T. A. Creighton. 5: 79-82.

** Hetman M, Xia Z (2000) Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta Neurobiol. Exp. 60:531-545.

Xia, Z. and Storm, D. R. (2002) CaRF, a Neuronal Transcription Factor that CaREs. Neuron 33: 315-316.

Xia Z, Storm DR. (2005)  The role of calmodulin as a signal integrator for synaptic plasticity. Nat. Rev. Neurosci. 6(4):267-76.

**Dirocco, DP and Xia, Z (2007) Alpha males win again. Nat Neurosci. 10(8): 938-40.

** Won-Seok Choi*, Heather M Klintworth*, Zhengui Xia. JNK3-Mediated Apoptotic Cell Death in Primary Dopaminergic Neurons. Methods Mol Biol. 2011;758:279-292.

PMID: 21815073

C. Books

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

Review date: 
9/24/2014