Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development

Singh, Karun K.; Ge, Xuecai; Mao, Ying; Drane, Laurel; Meletis, Konstantinos; Samuels, Benjamin Adam; Tsai, Li Huei

doi:10.1016/j.neuron.2010.06.002

Cited by 131 publications

(129 citation statements)

References 51 publications

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“…Our studies in mouse hippocampi and in C. elegans motor neurons together also show that DISC1 plays a role in regulating axonal connections (9). Because DISC1 is involved in essentially all aspects of neurodevelopment (4-7, 11), and because more than a dozen cytosolic proteins are reported to interact with DISC1 (6, 8,[28][29][30], it is likely that DISC1 acts as a scaffold protein inside neurons, recruiting various signaling components to exert its specific function at different developmental stages. It is therefore not surprising that, in contrast to our results, DISC1 has recently been reported to interact with another RAC1-GEF, Kalirin-7, and to inhibit the RAC1 signaling during dendritic spine morphogenesis (31).…”

Section: Discussionmentioning

confidence: 52%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

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Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and wellcharacterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.genetic model | rolipram S chizophrenia is a neurodevelopmental disorder with genetic predispositions (1, 2). Although the etiology and neuropathology of schizophrenia are still elusive, functional and neuroanatomical studies from patients have documented various abnormalities in the diseased brain. In particular, defects in neuronal connectivity during development have been proposed as an important precipitating factor for schizophrenia, which is thought to be unmasked by other developmental events or environmental stressors later in life (3). It is therefore likely that some of the major schizophrenia susceptibility genes are important for regulating axonal connections during development.In recent years, the effort to search for genes susceptible to schizophrenia has led to the identification of the Disrupted-inSchizophrenia 1 (DISC1) gene, whose mutation is highly associated with schizophrenia and other major human mental diseases (4). DISC1 has roles in neuron proliferation, neuron migration, axon outgrowth, and synapse formation/maturation (5-8). In our previous studies, we identified an unexpected role of DISC1 in regulating the guidance of developing axons in the adult-born hippocampal dentate granule cells (5, 9). These effects expand the known functions of DISC1 but sheds little light on how DISC1 effects axon guidance.To systemically study the role of DISC1 in axon guidance and to identify the signaling pathways that might be involved, we set out to establish a heterologous genetic system in the nematode Ca...

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Section: Discussionmentioning

confidence: 52%

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Chen

Huang

Cheng

2011

Proc. Natl. Acad. Sci. U.S.A.

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“…As DISC1 regulates neurogenesis and neuronal migration, we hypothesized that aberrant neuronal distribution in the cortex may be due to DISC1-mediated effects on both processes (Kamiya et al, 2005;Mao et al, 2009). It was recently shown that DISC1 may participate in neurogenesis and neuronal migration via separate and distinct signaling pathways (Singh et al, 2010). Abnormal cortical cytoarchitecture may also result from malfunctioning of the cytoskeletal machinery mediating neuronal migration.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental evidence is accumulating for the role of DISC1 in neuronal proliferation and neuronal migration (Kamiya et al, 2005;Mao et al, 2009;Singh et al, 2010). We therefore examined the number of neurons throughout the neocortex along the medial-lateral axis.…”

Section: Fewer Neun-positive Neurons In Q31l and L100p (؊/؊) Mutant Micementioning

confidence: 99%

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

Lee¹,

Fadel²,

Preston-Maher³

et al. 2011

J. Neurosci.

117

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Disrupted-in-Schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.

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“…Additionally, ASPM overexpression, like many Wnt-activating components, is associated with increased cell proliferation and tumor development, supporting a common effect on proliferation (Kouprina et al 2005;Hagemann et al 2008;Klaus and Birchmeier 2008;Lin et al 2008;Bikeye et al 2010;Vulcani-Freitas et al 2011). On the other hand, decreased expression of the schizophrenia risk gene Disc1 or its binding partner, Dixdc1, results in diminished Wnt signaling activity with accompanying deficits in embryonic and adult cortical neurogenesis (Mao et al 2009;Singh et al 2010).…”

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confidence: 94%

ASPM regulates Wnt signaling pathway activity in the developing brain

Buchman¹,

Durak²,

Tsai³

2011

Genes Dev.

Self Cite

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Autosomal recessive primary microcephaly (MCPH) is a neural developmental disorder in which patients display significantly reduced brain size. Mutations in Abnormal Spindle Microcephaly (ASPM) are the most common cause of MCPH. Here, we investigate the underlying functions of Aspm in brain development and find that Aspm expression is critical for proper neurogenesis and neuronal migration. The Wnt signaling pathway is known for its roles in embryogenesis, and genome-wide siRNA screens indicate that ASPM is a positive regulator of Wnt signaling. We demonstrate that knockdown of Aspm results in decreased Wnt-mediated transcription, and that expression of stabilized b-catenin can rescue this deficit. Finally, coexpression of stabilized b-catenin can rescue defects observed upon in vivo knockdown of Aspm. Our findings provide an impetus to further explore Aspm's role in facilitating Wnt-mediated neurogenesis programs, which may contribute to psychiatric illness etiology when perturbed.

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Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development

Cited by 131 publications

References 51 publications

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

ASPM regulates Wnt signaling pathway activity in the developing brain

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