Molecular Basis of Schizophrenia
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 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).
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 have 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 by 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 in studying not only schizophrenia, but also additional psychiatric and neurodevelopmental disorders, such as lissencephaly, bipolar, and depression. The knowledge gained from this research will help broaden our understanding of the underlying neurodevelopmental disorders and assist in the identification of new treatments.
Meyer K.D., Morris J.A. (2009) Disc1 regulates granule cell migration in the developing hippocampus. Hum Mol Genet. Sep 1; 18(17):3286-97.
Drerup C.M., Wiora H.M., Topczewski J., Morris J.A. (2009) Disc1 regulates foxd3 and sox10 expression, affecting neural crest migration and differentiation. Development; 136 (15):2623-32.
Meyer K.D., Morris J.A. (2008) Immunohistochemical Analysis of Disc1 Expression in the Developing Postnatal and Adult Hippocampus. Gene Expression Patterns; Vol. 8 (7-8) 494-501.
Drerup C.M., Ahlgren S., Morris J.A. (2007). Expression profiles of ndel1a and ndel1b, two orthologs of the NudE-Like gene, in the zebrafish. Gene Expr. Patterns; 7(6): 672-679.
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; 24(1): 3-10.
Malathi K., Higaki K., Tinkelenberg A., Erdenitz N., Wilcox L., Balderes D., Almanzar D., Redican F., Khan S., Alcantara F., Carstea G., Morris J.A., Sturley S.L. (2004). The Conserved, Primordial Role of NPC Proteins is to Transport Sphingolipids. J. Cell Biol.; 64(4): 547-56.
Morris J.A., Kandpal G., Ma Lei, Austin CP. (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.
Austin C.P., Ky B., Ma L., Morris J.A. and Shughrue P.J. (2003). DISC1 (Disrupted-In-Schizophrenia 1) is expressed in limbic regions of the primate brain. NeuroReport: 14(7):951-4.
Ma L., Liu Y., Ky B., Shughrue P., Austin C.P., Morris J.A. (2002). Cloning and characterization of the mouse DISC1 gene, a potential susceptibility gene for schizophrenia. Genomics: 80(6): 662-672.
Blair I.P., Adams L.J., Badenhop R.F., Moses M.J., Scimone A., Morris J.A., Ma L., Austin C.P., Donald J.A., Mitchell P.B., Schofield P.R. (2002). A transcript map encompassing a susceptibility locus for bipolar affective disorder on chromosome 4q35. Mol Psychiatry: 7(8):867-73.
Figueroa D.J., Morris J.A., Ma L., Kandpal G., Chen E., Li Y., Austin C.A. (2002). Presenilin-dependent gamma-secretase activity modulates neurite outgrowth. Neurobiology of Disease: 9:49-60.