Understanding the role of DISC1 in psychiatric disease and during normal development

Abstract

The biology of schizophrenia is complex with multiple hypotheses (dopamine, glutamate, neurodevelopmental) well supported to underlie the disease. Pathways centered on the risk factor "disrupted in schizophrenia 1" (DISC1) may be able to explain and unite these disparate hypotheses and will be the topic of this mini-symposium preview. Nearly a decade after its original identification at the center of a translocation breakpoint in a large Scottish family that was associated with major psychiatric disease, we are starting to obtain credible insights into its function and role in disease etiology. This preview will highlight a number of exciting areas of current DISC1 research that are revealing roles for DISC1 during normal brain development and also in the disease state. Together these different threads will provide a timely and exciting overview of the DISC1 field and its potential in furthering our understanding of psychiatric diseases and in developing new therapies.

Figure 1.

Pedigree of the Scottish family showing inheritance of a balanced translocation (1;11) (q42; q14.3) and clinical diagnoses within the family [adapted with permission from Blackwood et al. (2001), their Fig. 1]. The translocation (carriers are indicted by a red arrow) is shown to be associated with a range of major psychiatric illnesses including schizophrenia, bipolar affective disorder, and major depression.

Figure 2.

Diagram depicting a possible scenario how assembly and misassembly of DISC1 could regulate its function. Of note, experimental data that were used to generate this diagram were obtained in different in vivo and in vitro systems and were to a large extent obtained with (C-terminal) DISC1 fragments; the diagram's purpose is to generate testable hypotheses rather than to depict a complete picture of DISC1 physiology.

Figure 3.

Knockdown of zebrafish DISC-1 protein function results in abnormal brain and impaired axonogenesis. Two antisense morpholino-modified oligonucleotides (MO), targeting splice sites, were injected at the one- to two-cell stage. The D1 MO lies between exons 1 and 2, and ablates all functional DISC-1 protein, while the D2 MO lies between exons 8 and 9 and produces a truncated protein. Embryos were assayed at 24 h after fertilization in 4–6 independent experiments, with at least 100 embryos per experiment. Brain ventricles were visualized after microinjecting a fluorescent dye, rhodamine–dextran, into the hindbrain ventricle of living anesthetized embryos. A–D, DISC1 morpholino 1 (D1MO)-injected embryos display one of two phenotypes. The D1MO mild phenotype shows reduced brain ventricles with loss of normal shape (A) and defects in the somites and head (B). The D1MO strong phenotype shows abnormal brain (C) and no tail formation (D). E, F, Control morpholino (CMO)-injected embryos display a wild-type phenotype. G, H, Embryos injected with the D2MO display reduced hindbrain and midbrain ventricles (G) and reduced and bent tail (H). f, Forebrain; m, midbrain; h, hindbrain; asterisk, otic vesicles. I–K, Abnormal axon growth in D1 and D2 morphants, stained for differentiated neurons with anti-acetylated tubulin. Dorsal view of the hindbrain is shown. I, Control animals. J, Strongly reduced and disorganized axon growth in D1MO-injected embryos. K, Reduction of axons in D2MO-injected embryos.

Figure 4.

DISC1 regulates neurogenesis via Wnt/β-catenin signaling. During canonical Wnt signaling, β-catenin levels are kept low in the cytosol due to GSK3β-mediated phosphorylation which targets β-catenin for degradation. In the presence of Wnt ligands, the receptor complex and downstream signaling machinery is engaged, leading to increased accumulation of β-catenin and transcription of Wnt-dependent genes. In embryonic and adult neural progenitors, DISC1 directly binds and inhibits the function of GSK3β, thereby increasing cytosolic β-catenin concentration and functioning as a positive regulator of Wnt signaling. This function of DISC1 is similar to Akt and Lithium (used to treat mood disorders), which can also inhibit GSK3β, suggesting this pathway plays an important role in psychiatric disease.

Figure 5.

DISC1 at the centrosome. DISC1 is now known to bind to a number of proteins localized to the centrosome including nudE nuclear distribution gene E homolog (A. nidulans)-like 1 (NDEL1), pericentriolar material 1 (PCM1), and Bardet-Biedl syndrome proteins (BBSs). DISC1 play a role in anchoring these molecules in association with the dynein motor complex and centrosome, regulating microtubule organization. Of note, several of these DISC1 interactors at the centrosome are promising genetic risk factors for major mental illnesses in their own right.

Figure 6.

Model of DISC1 at the synapse. Multiple pieces of evidence show that DISC1 is a component of the postsynaptic density (PSDs) of excitatory synapses and regulates their form and function. It is likely that the effects of DISC1 are mediated through a range of protein interaction partners. The function of complexes of DISC1 and PSD proteins Kalirin-7 (kal-7) and Traf- and nck-interacting kinase (TNIK) are currently being elaborated. Kal-7 and TNIK both regulate the actin cytoskeleton, but it is currently unknown whether these two complexes act in a common pathway or independently of each other.