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Biography

Dr. Zhou received his PhD degree from Institute of Molecular Biology, Chinese Academy of Agricultural Sciences, Beijing. He completed his postdoctoral training in mouse molecular genetics at Robert Wood Johnson Medical School-UMDNJ and UCSD. Dr. Zhou was appointed as an Assistant professor in 2009, and has been the principal investigator on research grants from NIMH and NARSAD.

Research Interests

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.

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. 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 the DISC1-Boymaw fusion protein, predominantly localized in mitochondria, 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. The humanized mice display behaviors related to schizophrenia and depression. Dysregulation of protein translation has been documented in several mental disorders including fragile X mental retardation and autism. Optimal level of protein translation may be essential for neural plasticity. Expression of the DISC1-Boymaw fusion gene reduces protein translation and thereby contributes to the pathogenesis of major psychiatric disorders.