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DISC1 2010—Development in Flies, Humans, and Mice in Between

As part of our ongoing coverage of DISC1 2010, held 3-6 September 2010, in Edinburgh, the United Kingdom, we bring you a meeting missive from Antonio Rampino, a postdoctoral fellow at the University of Edinburgh.

24 September 2010. The second session in the theme Neurodevelopment and Model Systems was chaired by Professor Alcino Silva, University of California, Los Angeles, and opened with a talk by Hongjung Song of Johns Hopkins University, Baltimore, Maryland, entitled “Regulation of dentate granule cell development by DISC1.” In the first part of his presentation, Song showed a series of studies demonstrating that hippocampal dentate granule cells form a lifelong regenerating tissue in the context of which new cells are continuously born during the lifespan. Both internal and environmental stimuli contribute to regulate such a regeneration process, and the focus of Song’s discussion was on the role of DISC1 as an intrinsic factor in such a process. Previous work by Song’s group has clarified that DISC1 functions to downregulate the development of newborn dentate granule cells, possibly through its diverse interactions with NDE1, FEZ1, and AKT/mTOR-girdin (see SRF related news story; SRF news story), and that GABA-mediated depolarization of these neurons enhances their maturation and integration in the adult hippocampus. Here, Song presented data showing how DISC1 and GABA actually operate together in the fine regulation of such processes. Song reported that a precocious dendritic growth, inducible by DISC1 knockdown during adult neurogenesis in hippocampal neurons, requires NKCC1-dependent depolarizing GABA signaling in these neurons. Such regulation of dendritic growth is detectable in adult but not in early postnatal hippocampus neurogenesis, suggesting a critical role of neurodevelopment timing in DISC1-GABA-NKCC1 coordinated action. He also cited evidence from Daniel Weinberger's group at NIMH that DISC1 rs1000731 and NKCC1 rs10089 variants show an epistatic interaction in regulating neuronal growth and in inducing risk for schizophrenia.

Finally, Song mentioned an ongoing study exploring the role of DISC1 in human neurogenesis in a patient-derived iPS cell context. iPS cells were obtained by Russell Margolis of Johns Hopkins from a family of patients with a C-terminal deletion of full-length DISC1 (+/-), and the pedigree from this family eventually showed an association between this DISC1 mutation and the presence of psychiatric conditions.

The second speaker of the day was Kozo Kaibuchi, from Nagoya University, who talked about the role of DISC1 as a cargo protein. Much evidence is already available about the role of DISC1 in neuronal migration through its interaction with NUDEL/LIS1, FEZ1, and GSK3 (see SRF related news story and SRF news story), and new data provide evidence that in rat hippocampal neurons, DISC1 regulates axonal transport of the NUDEL/LIS1/14-3-3 epsilon complex, Grb2, and girdin through kinesin-1. As a step forward, Kaibuchi’s group has evidence implicating DISC1 as cargo for RNA-binding molecules, including hematopoietic zinc finger (HZF), which participates in the dendritic localization of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) mRNA, SYNCRIP, and KIF5A. A series of experiments on rat hippocampal neurons showed that DISC1 colocalizes with KIF5A, SYNCRIP, HZF, and IP3R1-3’UTR RNA, and is co-transported with IP3R1-3’UTR RNA. DISC1 knockdown inhibits both this transport process and the BDNF-induced local translation of IP3R1 mRNA. At the same time, kinesin-1 interacts with DISC1, mediating the transport of DISC1 and IP3R1 mRNA along microtubules, thus suggesting that DISC1 with HZF binds IP3R1 mRNA and thereby regulates its dendritic transport as a cargo adaptor for local translational processes.

In the second half of his talk, Kaibuchi reported results from his group’s recent work on DISC1 homozygous knockout mice, showing surprising evidence that DISC1 total inhibition in these animals doesn’t produce any gross abnormality in brain cyto-architecture.

The following talk was given by Jill Morris, from Northwestern University, Chicago, and was entitled “Disc1 regulates the migration of embryonic-born granule cells in the developing hippocampus.” Morris opened her presentation by summarizing the existing evidence about the importance of hippocampal abnormalities in schizophrenia and the role that DISC1 could have in regulating neurodevelopmental processes in this area of the brain. In situ hybridization experiments in mouse hippocampal tissue show that DISC1 is strongly expressed in this tissue through different stages of neurodevelopment into adulthood, with a possible specific cell-type pattern of expression. Interestingly DISC1 is expressed in cells of the dentate migratory stream, whose migration is crucial for the integration into local hippocampal networks and the formation of the adult dentate gyrus. Moreover, reduction in DISC1 expression levels through an shRNA approach in mouse developing hippocampus was shown to proportionally reduce granule cell migration, a phenotype that was rescued by DISC1 overexpression. Cell proliferation and death were not affected by DISC1 knockdown, nor was pyramidal cells migration. Very interestingly, new unpublished data by Morris and colleagues show that targeting DISC1 shRNA knockdown on specific DISC1 isoforms reveals that the role of DISC1 in granule cells migration is isoform specific.

The last talk in this session was by Katsuo Furukubo-Tokunaga of the University of Tsukuba, Japan, and was entitled “Modeling schizophrenia in flies.” This interesting contribution to the conference brought new data regarding an unexplored field of psychiatric research. Furukubo-Tokunaga discussed the importance of having a genetically tractable model for schizophrenia and other mental disorders, and presented the particular case of Drosophila melanogaster. This model is particularly useful to study the effect of DISC1 manipulation because Drosophila do not possess a DISC1 gene. Furukubo-Tokunaga’s group introduced the human DISC1 gene into the fly, thus having the unique possibility to analyze the effect of the gene on a number of cognitive and behavioral phenotypes in vivo. Results from this experiment showed that DISC1 causes no gross anatomical abnormalities in the fly, while showing significant expression levels in the mushroom body, a brain area critical for involved in cognitive function in Drosophila. Furthermore, DISC1 expression in the fly’s brain was associated with increased sleep amount, suppression of axonal branching in neurons, and impairments in olfactory associative learning in the fly’s larvae.

Moreover, the use of DISC1 deletion constructs in this animal model made it possible to explore many previously unknown functional domains in the DISC1 protein.—Antonio Rampino.

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