DISC1 Regulates the Transport of the NUDEL/LIS1/14-3-3ε Complex through Kinesin-1

Abstract

Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3. 14-3-3 is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3 complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3 in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3 at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3 complex into the axons as a cargo receptor for axon elongation.

The DISC locus in psychiatric illness

“…43 This evidence favours a haploinsufficiency model of causation, and is supported by RNA interference experiments for DISC1, as outlined in subsequent sections. 27,66,75,87,88 DISC1 mRNA was also shown to be decreased in lymphoblastoid cells derived from bipolar subjects in comparison to control unaffected family members. 93 This decreased expression was associated with a 12 marker DISC1 risk haplotype spanning the full-length of the DISC1 gene; 93 however, this broad haplotype is most likely a surrogate for an as yet unidentified risk variant.…”

“…56,[65][66][67]69,71,75,76,[84][85][86][87][88][89][90] Evidence from studies of endogenous DISC1 strongly supports a cytoplasmic localization and endogenous DISC1 immunoreactivity has been shown to overlap with that of F-actin, 76 a-tubulin, 84,85 MAP2 85 and gelsolin 65 supporting an interaction between DISC1 and the cytoskeleton. Endogenous DISC1 has also been colocalized with markers of the mitochondria 56,65,71,85 and centrosome.…”

“…Endogenous DISC1 has also been colocalized with markers of the mitochondria 56,65,71,85 and centrosome. 66,75 In primary and established neuronal cell types, DISC1 expression is localized to the cell body, nucleus and neurites 56,65,69,85,87,88 (Figure 1c).…”

“…76,87,88 Some studies have reported changes in subcellular DISC1 expression, which are related to neuronal differentiation. DISC1 expression is augmented in differentiating rodent (PC12) cells and differentiation coincides with movement of the DISC1 protein from cytoplasmic puncta into neurite-like processes.…”

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

“…26,27 DISC1-NUDEL-LIS1 interaction has been implicated in neurite outgrowth in PC12 cells and axon elongation in primary neurons. [28][29][30] In addition, alterations in the interaction of DISC1 with phosphodiesterase 4B have been suggested to contribute to the pathogenesis of major mental disorders. 31 Possible outcomes of the translocation in the DISC1 gene include haploinsufficiency or the production of a mutant-truncated DISC1 protein.…”