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The etiologies for many behavioral and neurodevelopmental disorders are unknown. This is in part due to the difficulty in studying neurological diseases on a molecular level in humans and the uncertainties in developing animal models. Some neurodevelopmental disorders, such as, autism and schizophrenia have clear genetic contributions. Both are polygenic disorders with genetic heterogeneity. These factors along with inconsistent/inaccurate diagnosis have made the identification of susceptibility genes difficult. However, with the completion of the human genome project, innovations in genomic technologies and recent discoveries in psychiatric genetics, clear advances are being made in candidate gene identification. My research interests have centered on candidate gene discovery and characterization with the goal being to determine what role these genes and the proteins they encode play in the pathogenesis of behavioral and neurodevelopmental disorders. The long-range goal is to identify not just the genes but the cellular pathways involved in the pathogenesis of disorders, such as, schizophrenia. In addition, we aim to determine if these pathways can be modulated and thus therapeutics developed to treat those who suffer from these devastating diseases. Since the therapeutics developed would be targeted against the proteins and cellular pathways directly affected by the disease, they should be more effective with less toxic side effects than the currently available treatments.
A schizophrenia susceptibility gene, DISC1, was identified in a large Scottish family with members who suffered from schizophrenia (seven members), bipolar disorder (one member) and recurrent major depression (ten members). In family members, the DISC1 gene was shown to be disrupted resulting in a truncated protein. My group has been investigating the expression and potential function of full-length DISC1 protein along with the truncated protein at the translocation breakpoint. We have used multiple approaches to identify its cellular function and potential role in schizophrenia. We have employed basic cell biology, yeast two-hybrid, in situ hybridization, immunohistochemistry, microarray expression analysis and proteomics to characterize DISC1. In addition, in order to generate animal models, we cloned and characterized the mouse DISC1 ortholog, disc1 (Ma et al.; 2002).
To briefly summarize our data thus far, we have discovered that DISC1 is a perinuclear protein, which is phosphorylated, but not glycosylated or proteolytically processed. Truncation of the protein, as occurs in the human subjects with schizophrenia, disrupts the normal perinuclear pattern of DISC1 localization, producing instead a diffuse cytoplasmic distribution (Morris et al., 2003). DISC1 is expressed in a highly restricted region in the primate brain, most strongly in the hippocampus, cerebral cortex and amygdala (Austin et al., 2003). Upon cloning of the mouse ortholog, disc1, we determined that it is only 56% identical to the human, but leucine zipper domains and coiled-coil domains are conserved. In situ hybridization of disc1 in mouse brain showed its expression in a highly restricted pattern similar to that seen in primate brain, with highest expression in the hippocampal dentate gyrus, cerebral cortex, olfactory bulbs, and cerebellum. Ontogeny studies revealed that the expression in the hippocampus is prominent throughout development (Austin et al., 2004). GeneChip analyses reveal that DISC1 regulates expression of genes involved in neurite outgrowth and maintenance, and neuronal determination and differentiation (Morris et al., manuscript in preparation). Yeast two-hybrid studies reveal that DISC1 interacts physically with proteins involved in the cytoskeleton and its regulation. In particular, yeast two-hybrid studies have found that DISC1 interacts with NUDEL, a protein involved in neuronal migration, whereas TRUN-DISC1 does not interact with NUDEL (Morris et al., 2003).
In order to further test the mechanistic hypotheses of DISC1, we propose to investigate DISC1’s role in neurite outgrowth and migration in the model organisms, zebrafish and mouse. Zebrafish has been recognized as an important model for human development and disease. Due to its well-defined nervous system and short generation time, the zebrafish model provides us with the opportunity to expeditiously examine DISC1’s role in neurite outgrowth and migration in a whole organism. The studies using zebrafish will be complemented with mouse transgenic models. Mice generated will be characterized for neuropathology, such as, abnormal cerebral cortical laminar arrangement, apoptosis and abnormal hippocampal development, as well as behavioral deficits. These animals (zebrafish and mice) will be useful to study DISC1’s function in the cell and its role in the pathogenesis of schizophrenia, in particular, its role in neuronal development, neuronal migration and neurite outgrowth and to determine the functional difference between the full-length and truncated forms of the protein. In addition, they will be useful to study not only schizophrenia, but also additional psychiatric and neurodevelopmental disorders, such as, lissencephaly, bipolar and depression. The knowledge gained from this research will be valuable for understanding the basis underlying neurodevelopmental disorders and for identifying new treatments.
Publications:
Austin, C.P., Ky, B., Ma, L., Morris, J.A., Shughrue, P.J. (2004) Expression of Disc1, a schizophrenia associated gene, is predominant in the hippocampus throughout development. Neuroscience, 124 (1), 3-10.
Austin CP, Ky B, Ma L, Morris JA and Shughrue PJ. DISC1 (Disrupted-In-Schizophrenia 1) is Expressed in Limbic Regions of the Primate Brain. NeuroReport 2003 May 23;14(7):951-4.
Ma, L., Liu, Y., Ky, B., Shughrue, P.J., Austin, C.P. and Morris, J.A. (2002) Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). Genomics, 80, 662-672.
Millar, J.K., Wilson-Annan, J.C., Anderson, S., Christie, S., Taylor, M.S., Semple, C.A., Devon, R.S., Clair, D.M., Muir, W.J., et al. (2000) Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum. Mol. Genet., 9, 1415-1423.
Morris, J.A., Kandpal, G., Ma, L., Austin, C.P. (2003) DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum. Mol. Genet., 12:1591-1608.
