Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth

Abstract

Disrupted-In-Schizophrenia 1 (DISC1) was identified as a novel gene disrupted by a (1;11)(q42.1;q14.3) translocation that segregated with schizophrenia in a Scottish family. Predicted DISC1 product has no significant homology to other known proteins. Here, we demonstrated the existence of DISC1 protein and identified fasciculation and elongation protein zeta-1 (FEZ1) as an interacting partner of DISC1 by a yeast two-hybrid study. FEZ1 and its nematode homolog are reported to represent a new protein family involved in axonal outgrowth and fasciculation. In cultured hippocampal neurons, DISC1 and FEZ1 colocalized in growth cones. Interactions of these proteins were associated with F-actin. In the course of neuronal differentiation of PC12 cells, upregulation of DISC1/FEZ1 interaction was observed as along with enhanced extension of neurites by overexpression of DISC1. The present study shows that DISC1 participates in neurite outgrowth through its interaction with FEZ1. Recent studies have provided reliable evidence that schizophrenia is a neurodevelopmental disorder. As there is a high level of DISC1 expression in developing rat brain, dysfunction of DISC1 may confer susceptibility to psychiatric illnesses through abnormal development of the nervous system.

Differential gene expression profiles of neurothekeomas and nerve sheath myxomas by microarray analysis

“…[37][38][39][40][41][42][43][44][45][46][47][48] The principal differentially expressed genes upregulated in neurothekeomas and cellular fibrous histiocytomas over nerve sheath myxomas and schwannomas consisted of those encoding various metalloproteinases and glycoproteins. These genes are involved in extracellular matrix growth and remodeling, and cell adhesion in fibroblasts and macrophages (Table 6).…”

Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia

“…25,26,34 Thus, we evaluated the effects of mutant hDISC1 on mouse neurodevelopment. Expression of mutant hDISC1 was not associated with gross developmental defects in suckling mice or alterations in breeding and nesting behavior in adult mice.…”

“…[18][19][20] DISC1 protein likely acts as a scaffold protein, with multiple motifs mediating binding to several proteins and facilitating formation of protein complexes. [21][22][23][24] The DISC1 protein interactors include microtubule-interacting protein associated with tumor necrosis factor receptor associated factor-3, microtubule-associated protein 1A, 23 fasciculation and elongation protein zeta-1 25 and NudE-like (NUDEL) protein. 21,23 DISC1 has been suggested to exist in a neurodevelopmentally regulated protein complex with NUDEL and LIS1.…”

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

“…16 Overexpression of normal DISC1 may increase neurite outgrowth. 21 DISC1 is localized to multiple subcellular domains, including the cytoskeleton, mitochondria, and nucleus. 7,16,22 The C-terminal region of DISC1 apparently lost in the Scottish pedigree following translocation, and especially the final coiled-coil region defined by amino acids 807-828, appears to be important for an interaction between DISC1 and Nudel.…”