Severe psychiatric illnesses, such as schizophrenia and bipolar affective disorder, are chronic and generally disabling brain diseases in need of effective treatments. They affect a large portion of the world's population and have devastating consequence for the sufferers, their families and for the society as a whole. While their etiology is largely unknown, accumulative evidence support the view that schizophrenia is a disease of neuronal development. A number of susceptibility genes have recently been identified from human genetic association studies. One gene named disrupted-in-schizophrenia 1 (DISC1), was identified at the breakpoint of a balanced (1;11)(q42;q14) translocation that co-segregates with schizophrenia and other major affective disorders in a large Scottish family. Recently we have provided evidence to support a critic role of DISC1 in multiple aspects of adult neurogenesis in rodents, including neuronal morphogenesis, migration, axon and dendritic development, and synapse formation of newborn neurons in the adult brain. However, DISC1 gene is not well conserved between humans and rodents and the function of DISC1 in human embryonic neurogenesis and neural development is currently unknown. Recent success in reprogramming human skin fibroblasts into pluripotency (induced-pluripotent stem cells or iPSCs) paves the way to study human development and to discover the molecular basis of human diseases in more relevant experimental systems using human cells. Differentiation of iPSCs derived from schizophrenia patients into neurons and glia may revolutionize our ability to investigate molecular and cellular mechanisms underlying schizophrenia, including both genetic and sporadic origins. We have generated human iPSCs from patients with genetic disorders. We have also developed a battery of methodologies to examine the differentiation, functional maturation and integration of neurons derived from stem cell both in vitro and in vivo, including immunocytochemistry, confocal and electron microscopy, electrophysiology, and transplantation. In the current project, we aim to establish a platform using patient-derived iPSCs and their neural progeny to identify neurodevelopmental defects associated with schizophrenia and to understand functions of schizophrenia susceptibility genes in human neuronal development. During the R21 phase, we will derive and characterize iPSCs from both genetic (with DISC1 mutations) and sporadic schizophrenia patients and control subjects. During the R33 phase, we will examine the neuronal developmental defects of patient-derived iPSCs using established in vitro and in vivo analysis. Our proposed study may provide novel insight into mechanisms underlying these susceptibility genes in affecting human neurodevelopment and a better understanding of the etiology and pathogenesis of schizophrenia and other related major mental illnesses. Our study may lead to generation of new experimental models of human psychiatric diseases to be tested with potential therapeutic molecules.
Recent advances in human stem cell biology offer exciting possibility to investigate functions of disease genes and to model human diseases using relevant human cell types. We will establish a platform using patient-derived iPSCs to understand functions of schizophrenia susceptibility genes in regulating human neurogenesis under normal and disease state, a topic not accessible with traditional animal model systems. Our study will provide fundamental information on functions of susceptibility genes of mental disorders in human neurodevelopment and may reveal the etiology and pathogenesis of these disorders.
| Ye, Fei; Kang, Eunchai; Yu, Chuan et al. (2017) DISC1 Regulates Neurogenesis via Modulating Kinetochore Attachment of Ndel1/Nde1 during Mitosis. Neuron 96:1041-1054.e5 |
| Yoon, Ki-Jun; Song, Guang; Qian, Xuyu et al. (2017) Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins. Cell Stem Cell 21:349-358.e6 |
| Oh, Yohan; Zhang, Feiran; Wang, Yaqing et al. (2017) Zika virus directly infects peripheral neurons and induces cell death. Nat Neurosci 20:1209-1212 |
| Yoon, Ki-Jun; Ringeling, Francisca Rojas; Vissers, Caroline et al. (2017) Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell 171:877-889.e17 |
| Zeng, Yaxue; Yao, Bing; Shin, Jaehoon et al. (2016) Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. Mol Cell 61:153-60 |
| Wen, Zhexing; Christian, Kimberly M; Song, Hongjun et al. (2016) Modeling psychiatric disorders with patient-derived iPSCs. Curr Opin Neurobiol 36:118-27 |
| Shin, Jaehoon; Ming, Guo-li; Song, Hongjun (2015) Seeking a roadmap toward neuroepigenetics. Neuron 86:12-5 |
| Brennand, Kristen J; Marchetto, M Carol; Benvenisty, Nissim et al. (2015) Creating Patient-Specific Neural Cells for the In Vitro Study of Brain Disorders. Stem Cell Reports 5:933-945 |
| Yu, Huimei; Su, Yijing; Shin, Jaehoon et al. (2015) Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nat Neurosci 18:836-43 |
| Song, Hongjun; Ming, Guo-Li (2014) Reprogram to pluripotency: a new logic and a chemical cocktail. Natl Sci Rev 1:6-7 |
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