Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site

The DISC locus in psychiatric illness

“…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. 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).…”

“…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).…”

“…65 DISC1 subcellular expression by fluorescence microscopy has mainly been described as punctate, granular or aggregate within the cytoplasm, and filamentous in association with the mitochondria. 65,67,71,76,[84][85][86] In contrast, C-terminally truncated forms of DISC1 are commonly reported as diffusely localized within the cytoplasm. 56,66,67,71,85 Amino acids 1-358 (the 'head' domain) of DISC1 are important for DISC1 localization to the nucleus, 71 and regions within the C-terminal tail of the protein are particularly important for DISC1s cytoskeletal and centrosomal localization, as DISC1 truncates lacking portions of the C-terminus generally exhibit diminished localization to the cytoskeleton and centrosome 66,67,71,85,86 (Table 3b).…”

“…84 This interval overlaps substantially with the period of active neuronal migration within the developing cortex. DISC1 localizes to the centrosome, 66,67 the key organelle for control of microtubule dynamics, and also associates with microtubules, 67,84,85 suggesting it may have a key role in LIS1/NDEL1-related microtubule dynamics. Furthermore, overexpression of a Cterminally truncated form of DISC1 termed mutDISC1 (which lacks the NDEL1-and LIS1-binding region 56,67,75,84 ), disrupts the accumulation of LIS1, NDEL1, dynein and dynactin at the centrosome.…”

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

“…21,23 DISC1 has been suggested to exist in a neurodevelopmentally regulated protein complex with NUDEL and LIS1. 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.…”