Editors' ChoiceNeuroscience

A Scaffold for Neurodevelopment

Science Signaling  22 Nov 2011:
Vol. 4, Issue 200, pp. ec324
DOI: 10.1126/scisignal.4200ec324

Mutations in the gene encoding Disrupted in Schizophrenia 1 (DISC1), a scaffolding protein that binds to numerous partners and has been implicated in brain development, are associated with increased risk for various neuropsychiatric disorders (see Wexler and Geschwind). Now, two groups, Singh et al. and Kang et al., have identified mechanisms whereby DISC1 variants might contribute to abnormalities of neurodevelopment.

Noting that DISC1 inhibits GSK-3β (glycogen synthase kinase 3β), thereby activating the canonical Wnt signaling pathway, which plays a prominent role in brain development, Singh et al. explored the effects of three common (R264Q, L607F, and S704C) and one rare (A83V) human DISC1 variants identified by deep sequencing on Wnt signaling in mouse, zebrafish, and human model systems. Whereas wild-type DISC1 (WT-DISC1) potentiated Wnt signaling in human embryonic kidney (HEK) 293 cells, rescued the effects on Wnt signaling of DISC1 knockdown in mouse carcinoma cells, and stimulated proliferation of neuroblastoma cells (an effect blocked by a dominant-negative form of a transcription factor downstream of the Wnt pathway), as did the S704C variant, the R264Q, L607F, and A83V variants did not. In vivo analyses indicated that R264Q and L607F were ineffective at rescuing neurodevelopmental defects consistent with decreased Wnt signaling in mouse and zebrafish; indeed, analyses of R264Q overexpression in embryonic mouse brain suggested that it might act as a dominant-negative factor. In contrast, S704C was associated with impaired neuronal migration (a Wnt-independent phenotype) in the developing cortex. Immunoprecipitation analysis of HEK 293 cells transfected with tagged forms of the DISC1 variants indicated that R264Q, L607F, and A83V showed decreased association with GSK-3β after stimulation with Wnt3a compared with WT-DISC1 or the S704C variant. Human lymphoblast cell lines (LCLs) homozygous for RR264 showed enhanced Wnt signaling compared with those homozygous for 264QQ and, within a given genotype (that is, RR264 or 264QQ), Wnt activity in LCLs from bipolar individuals was decreased compared with that from controls.

In the second study, Kang et al. investigated the role of DISC1 interactions with two other binding partners, FEZ1 (Fasciculation and elongation protein zeta-1) and NDEL1 (nuclear distribution gene E-like homolog 1), in adult mouse neurogenesis. FEZ1 knockdown increased soma size and dendrite length and complexity of newborn granule cell neurons in the dentate gyrus of adult mice, a subset of the abnormalities seen with DISC1 knockdown. Combined knockdown of DISC1 and FEZ1 had a synergistic effect on dendrite growth, and the FEZ1 knockdown phenotype was mimicked by a peptide that inhibited the interaction between DISC1 and FEZ1. NDEL1 knockdown led to development of ectopic dendrites and abnormal localization of the cell body, another set of abnormalities seen with DISC1 knockdown. Combined knockdown of NDEL1 and FEZ1 had additive, rather than synergistic, effects, suggesting their involvement in different aspects of neuronal development, and coimmunoprecipitation combined with knockdown of the individual proteins indicated that FEZ1, DISC1, and NDEL1 existed in a complex, with DISC1 required for the association of FEZ1 and NDEL1. Whereas genetic analyses identified no association of FEZ1 variants with schizophrenia per se, an epistatic interaction was identified between a FEZ1 variant and DISC1 S704C. Together, the two studies provide insight into the complex mechanisms whereby DISC1 variants may influence neurodevelopment and the risk for neuropsychiatric disorders.

K. K. Singh, G. De Rienzo, L. Drane, Y. Mao, Z. Flood, J. Madison, M. Ferreira, S. Bergen, C. King, P. Sklar, H. Sive, L.-H. Tsai, Common DISC1 polymorphisms disrupt Wnt/GSK3β signaling and brain development. Neuron 72, 545–558 (2011). [Online Journal]

E. Kang, K. E. Burdick, J. Y. Kim, X. Duan, J. U. Guo, K. A. Sailor, D.-E. Jung, S. Ganesan, S. Choi, D. Pradhan, B. Lu, D. Avramopoulos, K. Christian, A. K. Malhotra, H. Song, G.-l. Ming, Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. Neuron 72, 559–571 (2011). [Online Journal]

E. M. Wexler, D. H. Geschwind, DISC1: A schizophrenia gene with multiple personalities. Neuron 72, 501–503 (2011). [Online Journal]