Xianjin Zhou, Ph.D.

Assistant Professor of Psychiatry,
University of California San Diego.

University of California San Diego
9500 Gilman Drive, MC0603
La Jolla, CA. 92093
Office: 858-822-3709
email: xzhou@ucsd.edu

Faculty research interest/specialization

Molecular mechanisms of psychiatric disorders.

Profile

As a molecular biologist, I am interested in understanding molecular mechanisms underlying human psychiatric disorders. With the funding support of NMIH R01 and R21 grants, we have generated several humanized mouse lines expressing different susceptibility genes including Sp4, DISC1-Boymaw fusion gene, and COMT Met/Val. The molecular mechanisms and pathways of the susceptibility genes have been studied at molecular, cellular, and system levels. We are currently focusing on the following two genes:

Sp4 Gene
Sp4 gene encodes a neuron-specific transcription factor that binds GC-rich DNA in the promoter of most genes. Its expression begins from E9.5 during mouse embryogenesis and persists throughout the adulthood. Sp4 knockout mice displayed reduced hippocampal size, subtle hippocampal vacuolization, as well as impaired postnatal development of hippocampal dentate gyrus. Sp4 hypomorphic mice displayed schizophrenia endophenotypes including PPI deficit, learning and memory deficit, and exaggerated responses to NMDAR antagonists. Human SP4 gene was deleted in patients with schizophrenia. We are conducting genetic rescue experiments to restore Sp4 gene expression in excitatory and GABAergic inhibitory neurons with EMX1-Cre and Dlx6a-Cre respectively to dissect out neural circuits modulating the behavioral deficits.

DISC1-Boymaw Fusion Gene
A balanced chromosome translocation was identified in a large Scottish schizophrenia and major depression family. The t(1; 11) translocation appears to be the causal genetic lesion with 70% penetrance for schizophrenia and major depression. Therefore, investigation of molecular mechanisms underlying schizophrenia and major depression in the Scottish family will be invaluable for our understanding of the molecular basis of these major psychiatric disorders which we currently have no biological hallmarks for diagnosis. Molecular studies identified the disruption of the DISC1 gene by the chromosome translocation at chromosome 1q42. However, no gene was found to be disrupted by the other breakpoint at chromosome 11q14.3. Therefore, the disruption of the single DISC1 gene has been assumed to contribute to the pathogenesis of schizophrenia and major depression. However, our analysis found that a novel gene, Boymaw, was also disrupted by the translocation at chromosome 11q14.3, and the DISC1-Boymaw fusion genes were generated. We found that that expression of the DISC1-Boymaw fusion gene inhibits both intracellular NADH oxidoreductase activities and protein translation. We generated humanized DISC1-Boymaw mice with gene targeting to examine the in vivo functions of the fusion genes. Consistent with the in vitro studies on the DISC1-Boymaw fusion gene, both oxidoreductase activities and protein translation are decreased in the brains of the humanized mice. Expression of GAD67, NMDAR1, and PSD95 proteins are also reduced. The humanized mice display prolonged and increased responses to the NMDA receptor antagonist, ketamine, on various mouse genetic backgrounds, mimicking phenotypes of schizophrenia. Abnormal information processing of acoustic startle and depressive-like behaviors are also observed. Dysregulation of protein translation has been documented in several mental disorders including fragile X mental retardation and autism. Expression of the DISC1-Boymaw fusion gene may reduce protein translation of genes critical in NMDA and GABA neurotransmissions as well as synaptogenesis in the pathogenesis of major psychiatric disorders.

Collaborators

Mark Geyer
John Kelsoe
Victoria Risbrough
Jared Young


Susan Powell
Terrence Sejnowski
Margarita Behrens

Primary Publications

Ji, B., Wang, X., Pinto-Duarte, A., Kim, M., Caldwell, S., Young, JW., Behrens, MM., Sejnowski, TJ., Geyer, MA., Zhou, X, (2013). Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia. PLoS ONEI 8(6):e66327

Kim,M., Soontornniyomkij,V., Ji, B., Zhou, X., (2012). System-wide immunohistochemical analysis of protein co-localization. PLoS ONE 7(2) :e32043.

Zhou, X., Nie, Z., Roberts, A., Zhang, D., Sebat, J., Malhotra, D., Kelsoe, JR., Geyer, MA. (2010). Reduced NMDAR1 expression in the Sp4 hypomorphic mouse may contribute to endophenotypes of human psychiatric disorders. Human Molecular Genetics 19(19):3797-805. PMCID: PMC2935857

Zhou, X., Chen, Q., Schaukowitch, K., Kelsoe, JR., Geyer, MA. (2010). Insoluble DISC1-Boymaw Fusion Proteins Generated by the DISC1 Translocation. Molecular Psychiatry 15(7):669-72. PMC204612

Zhou, X., Tang, W., Greenwood, T., Guo, S., He, L., Geyer, MA., Kelsoe, JR. (2009). Transcription Factor SP4 as A Susceptibility Gene for Bipolar Disorder. PLoS ONE 4(4) e5196. PMCID: PMC2674320

Zhou, X., Barrett, T., Kelsoe, JR. (2008). Promoter Variant In The GRK3 Gene Associated With Bipolar Disorder Alters Gene Expression. Biological Psychiatry 64(2):104-10. PMCID57036

Zhou, X., Geyer, MA., Kelsoe, JR. (2008). Does Disrupted-in-schizophrenia (DISC1) Generate Fusion Transcripts. Molecular Psychiatry 13(4):361-3. PMCID: PMC2771200.

Zhou, X., Qyang, Y., Kelsoe, JR., Chien, KR., Geyer, MA. (2007). Impaired Postnatal Development of Hippocampal Dentate Gyrus in Sp4 Null Mutant Mice. Genes, Brain and Behavior 6(3):269-276 PMID: 16899055

Zhou, X., Long, JM., Geyer, MA. , Masliah, E., Kelsoe, JR., Wynshaw-Boris, A., Chien, KR. (2005). Reduced expression of the Sp4 gene in mice causes deficits in sensorimotor gating and memory associated with hippocampal vacuolization. Molecular Psychiatry 10(4):393-406. PMID: 15558077