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DISC1 Roundup: Of Mice, Men, and … Amoebas?

20 December 2011. The disrupted-in-schizophrenia-1 (DISC1) protein is becoming one of those nexus molecules for brain function, and a slew of studies published over the past six months reveals new complexities. Though DISC1 is already appreciated for its diverse roles in brain development and function, new findings from humans, mice, zebrafish, and even the humble amoeba offer new insights, confirm older ones, and in some cases, contradict previous findings. One emerging theme is that the type of experimental manipulation matters, with transgenic approaches to changing DISC1 levels sometimes coming to different conclusions from acute, RNAi-mediated changes.

Ever since a chromosomal translocation that disrupts the DISC1 gene was discovered in a Scottish family beset by schizophrenia and other major mental illnesses 10 years ago, researchers have been vigorously piecing together DISC1’s function (Brandon and Sawa, 2011). As a scaffold protein, DISC1 acts as a hub of protein-protein interactions which seem to mediate DISC1’s multiple roles, including neurogenesis (see SRF related news story), neuronal migration (see SRF related news story), dendrite and axon growth, and synapse formation (Wang et al., 2011). The new findings highlight additional roles for DISC1 function in synaptic plasticity, non-canonical Wnt signaling, regulation of phosphorylation switches on interacting proteins, axon targeting, glia cells, and vesicle transport.

DISC1 removal
One approach to pinning down DISC1 function is to explore what happens when it is removed, and a DISC1 knockout mouse has just arrived on the scene in a study in Human Molecular Genetics. Created by Kozo Kaibuchi and colleagues at Nagoya University in Japan, this mouse joins the ranks of other DISC1 mutants that either carry missense mutations (Clapcote et al., 2007; see SRF related news story) or overexpress truncated forms of DISC1 (e.g., Hikida et al., 2007; see SRF related news story). Because all reported splice variants of DISC1 contain exons 2 and 3, and because these regions contain binding sites for many of DISC1’s interacting proteins, Kaibuchi’s team sought a loss-of-function DISC1 mouse—or something very close to it—by deleting exons 2 and 3 of the gene. These mice lacked the major, 100 kDa isoform of DISC1 corresponding to the full-length protein, and while unknown forms of DISC1 lacking exons 2 and 3 may still be present, they were not detected by new DISC1 antibodies also developed by Kaibuchi’s team. Their DISC1 antibodies seemed more specific than commercially available ones, and localized DISC1 near to the Golgi apparatus in hippocampal neurons and in astrocytes.

For such a drastic loss of DISC1, the mice seemed fairly normal. First authors Keisuke Kuroda, Shinnosuke Yamada, and Motoki Tanaka found no obvious abnormalities in brain morphology or structure—a finding at odds with the numerous reports of disrupted neurogenesis and migration with DISC1 knockdown (see SRF related news story), including a recent report of impaired migration of hippocampal pyramidal cells that had been depleted of DISC1 with RNAi (Tomita et al., 2011). The authors suggest that some kind of compensatory mechanisms may be at work which are not recruited in acute, RNAi-induced DISC1 disruptions. The researchers also found an increase in the threshold for inducing long-term potentiation in the hippocampus in these mice, and behaviorally, the mice exhibited typical “schizophrenia-like” abnormalities in sensorimotor gating and drug-induced hyperlocomotion. They also tended to be less anxious and slightly more social than controls, which doesn’t match up with previous studies, and conditional knockouts may resolve these discrepancies.

Sidestepping the behavioral consequences of DISC1 loss, Hazel Sive of Massachusetts Institute of Technology in Boston focused purely on development by using zebrafish as a tool for understanding DISC1 function. Writing in the December issue of the FASEB Journal, first author Gianluca De Rienzo and colleagues report that zebrafish lacking DISC1 developed brain and axon defects as well as misshapen muscles and tails. As found in previous studies (see SRF related news story), the nervous system defects were linked to DISC1’s involvement in Wnt pathway signaling, in which DISC1 suppresses the activity of glycogen synthase kinase 3β (GSK3β) and promotes neural proliferation. However, the new study found that the muscle and tail abnormalities reflected DISC1’s engagement with a non-canonical Wnt pathway involving proteins Daam1 and Rho—a previously unknown outlet for DISC1 and another mechanism to consider in neuropsychiatric conditions associated with DISC1.

Another new site of DISC1 action—this time of the phosphorylation type—came to light in a study of DISC1 and its myriad interacting proteins from a team led by Kirsty Millar and David Porteous of University of Edinburgh in the U.K. As reported in the Journal of Neuroscience, first author Nicholas Bradshaw and colleagues identified a phosphorylation site on nuclear distribution gene E homolog 1 (NDE1) whose phosphorylation status was sensitive to DISC1. DISC1 and phosphodiesterase 4 (PDE4) together spurred phosphorylation at this site, which resulted in altered binding between NDE1 and its partners, LIS1 and nudE nuclear distribution gene E homolog-like (NDEL1), and inhibited neurite outgrowth. Similar to a study earlier this year (see SRF related news story), the study identifies a phosphorylation switch that changes how the proteins surrounding DISC1 interact. Interestingly, phosphorylated NDE1 accumulated at certain spots within the cell, including the centrosome, the center for microtubule organization. This invokes a role for DISC1 in cytoskeleton form and function, an idea newly reviewed in Molecular and Cellular Neuroscience (Wang and Brandon, 2011).

Missed axon targets
Taking a more disease-focused approach, other studies have tried to simulate the human translocation, which interrupts the DISC1 gene in the middle. This results in short forms of the protein, which occur alongside normal-length versions from the undisrupted copy of the DISC1 gene. Though this might seem milder than a full-on knockout, some researchers have proposed that truncated DISC1 could do some damage by binding to normal copies of the protein, thereby preventing them from doing their job (see SRF related news story).

Joseph Gogos of Columbia University in New York and colleagues have studied an approximation of the human translocation in mice that carry a deletion within the middle of the DISC1 gene, and found some working memory deficits (see SRF related news story). In the latest installment on these mice, published in the Proceedings of the National Academy of Sciences, first authors Mirna Kvajo and Heather McKellar detail numerous cyto-architectural abnormalities among dentate granule cells of the hippocampus. Of note, the positioning of the axonal outputs of these cells, called mossy fibers, was disorganized, which suggests a problem with axon targeting in these mutants. Compared to controls, these mice also exhibited more transient short-term plasticity of the mossy fiber synapse onto its CA3 target, and higher levels of cAMP among granule cells—a finding that suggests that DISC1’s interaction with PDE4, an enzyme that degrades cAMP, is somehow compromised.

The researchers also noted that they did not find evidence for accelerated maturation, or overgrowth, of adult-born dentate granule cells, which have been found in RNAi-mediated gene silencing studies of DISC1 (see SRF related news story). Whether there is some compensatory mechanism at work in transgenic animals, or off-target effects of RNAi, these discrepancies again highlight potential differences between the two approaches.

Another study underscores a role for DISC1 in axon targeting, finding perturbations of DISC1 in people who lack a corpus callosum, the axon tract connecting the two sides of the brain. Published in the American Journal of Medical Genetics and led by Elliot Sherr of the University of California, San Francisco, the study found deletions of a region on chromosome 1 that contains DISC1 in individuals with a complete loss of corpus callosum. By resequencing DISC1 in 144 people with MRI-characterized corpus callosum deficits, first authors Nathan Osbun and Jiang Li also found 20 sequence alterations. Four of these were rare and potentially pathogenic, two were not found in over 700 controls, and one led to reduction of the long—but not short—forms of DISC1, much like the Scottish translocation. These findings support the idea that abnormal connectivity patterns between brain regions, and callosal malformations in particular, underlie psychiatric conditions, including schizophrenia (Arnone et al., 2008).

From oligodendrocytes to oligomers
Another strategy is to introduce human mutant DISC1 into the experimental paradigm of choice, and see what happens. Conditional expression of truncated forms of human DISC1 in the forebrain of mice developed by Mikhail Pletnikov of Johns Hopkins University, Baltimore, Maryland, results in numerous neural and behavioral deficits (see SRF related news story). But it doesn’t end there, according to a collaboration between Pletnikov's group and that of Vahram Haroutunian at the Mount Sinai School of Medicine in New York to examine glia cells in these mice. First author Pavel Katsel and colleagues found increased proliferation and premature differentiation of oligodendrocytes, the myelin-making glia cells. They also detected increased expression of neuregulin 1 and its receptors in these mutants.

DISC1 also has a hand in synaptic vesicle transport, according to a study published in Neuroscience Research from Toshifumi Tomoda of City of Hope Medical Center in Duarte, California. Using time-lapse video microscopy to observe the effects of introducing a truncated form of human DISC1 to mouse cortical cell cultures, first author Rafael Flores and colleagues observed seemingly stalled synaptic vesicles along microtubules, and this involved disruptions to the cargo-transporting protein machinery involving DISC1’s binding partner fasciculation and elongation protein zeta 1 (FEZ1) and synaptotagmin-1 (Syt-1). Interestingly, lithium could clear the synaptic vesicle logjam, and it also coaxed FEZ1 and Syt-1 back together. These results highlight the multi-protein complexes in which DISC1 participates and their sensitivity to the state of DISC1. Similarly, a recent study finds that even the common S704C risk variant of DISC1 results in improper formation of DISC1 oligomers, something that could translate into impaired interactions among its binding partners (Narayanan et al., 2011).

Clues by association
Other clues about the workings of DISC1 have emerged as byproducts of experiments that don’t tweak DISC1 directly. As reported in the Journal of Neurochemistry, a study from Shinichi Kohsaka of the National Institute of Neuroscience in Tokyo, Japan, found an experience-dependent component to DISC1 expression in the adult hippocampus. When first author Takashi Namba and colleagues injected mice with a blocker of NMDA receptors, this suppressed DISC1 expression and disrupted migration of newborn neurons. The migration deficit could be rescued by supplying extra DISC1, and suggests that neural activity itself regulates DISC1’s role in migration.

While investigating the function of densin-180, a scaffolding protein enriched within the post-synaptic density, a team led by Mary Kennedy of the University of California, Los Angeles, found a connection to DISC1. Knocking out the gene encoding densin-180 in mice decreased the amount of DISC1 and mGluRs localized in the post-synaptic density, without changing overall amounts of the proteins. In their Journal of Neuroscience paper, first authors Holly Carlisle, Tinh Luong, and Andrew Medina-Marino also report disruptions to glutamate-dependent plasticity and behavioral abnormalities related to schizophrenia, including hyperactivity, anxiety, prepulse inhibition deficits, and cognitive deficits. The researchers suggest that densin-180 helps keep components of the post-synaptic density, including DISC1, in the right place at excitatory synapses, and that removing it affects the network of proteins surrounding synapses and results in behaviors reminiscent of mental illness.

And finally, according to a report in Human Molecular Genetics, even amoebas can offer something to ponder in terms of DISC1 function. When Luis Sanchez-Pulido and Chris Ponting of the University of Oxford in the U.K. scanned genome sequences with a particular algorithm, they found DISC1 orthologs in invertebrates, including sea anemones, amoebas, even rice plants. These and the DISC1 orthologs found in some vertebrates share sequences resembling UVR domains, which form α-helices and are involved in protein-protein interactions. A common DISC1 variant (L607F) associated with schizophrenia lies within a UVR domain, and further evolutionary analysis may help flag the functional parts of the DISC1 protein.—Michele Solis.

Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet. 2011 Dec 1; 20: 4666-4683. Abstract

De Rienzo G, Bishop JA, Mao Y, Pan L, Ma TP, Moens CB, Tsai LH, Sive H. Disc1 regulates both β-catenin-mediated and noncanonical Wnt signaling during vertebrate embryogenesis. FASEB J. 2011 Dec; 25: 4184-4197. Abstract

Bradshaw NJ, Soares DC, Carlyle BC, Ogawa F, Davidson-Smith H, Christie S, Mackie S, Thomson PA, Porteous DJ, Millar JK. PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. J Neurosci. 2011 Jun; 31: 9043-9054. Abstract

Kvajo M, McKellar H, Drew LJ, Lepagnol-Bestel AM, Xiao L, Levy RJ, Blazeski R, Arguello PA, Lacefield CO, Mason CA, Simonneau M, O'Donnell JM, Macdermott AB, Karayiorgou M, Gogos JA. Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice. Proc Natl Acad Sci U S A. 2011 Dec; 108: E1349-58. Abstract

Osbun N, Li J, O'Driscoll MC, Strominger Z, Wakahiro M, Rider E, Bukshpun P, Boland E, Spurrell CH, Schackwitz W, Pennacchio LA, Dobyns WB, Black GC, Sherr EH. Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene. Am J Med Genet A. 2011 Aug; 155A: 1865-1876. Abstract

Katsel P, Tan W, Abazyan B, Davis KL, Ross C, Pletnikov MV, Haroutunian V. Expression of mutant human DISC1 in mice supports abnormalities in differentiation of oligodendrocytes. Schizophr Res. 2011 Aug; 130: 238-249. Abstract

Flores R 3rd, Hirota Y, Armstrong B, Sawa A, Tomoda T. DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway. Neurosci Res. 2011 Sep; 71: 71-77. Abstract

Namba T, Ming GL, Song H, Waga C, Enomoto A, Kaibuchi K, Kohsaka S, Uchino S. NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1). J Neurochem. 2011 Jul; 118: 34-44. Abstract

Carlisle HJ, Luong TN, Medina-Marino A, Schenker L, Khorosheva E, Indersmitten T, Gunapala KM, Steele AD, O'Dell TJ, Patterson PH, Kennedy MB. Deletion of Densin-180 Results in Abnormal Behaviors Associated with Mental Illness and Reduces mGluR5 and DISC1 in the Postsynaptic Density Fraction. J Neurosci. 2011 Nov 9; 31: 16194-16207. Abstract

Sanchez-Pulido L, Ponting CP. Structure and evolutionary history of DISC1. Hum Mol Genet. 2011 Oct 15; 20: R175-81. Abstract

Comments on News and Primary Papers
Primary Papers: PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1.

Comment by:  Atsushi Kamiya
Submitted 12 August 2011 Posted 12 August 2011

This paper from Millar and Porteous’s group (Bradshaw et al., 2011) proposes a mechanistic link between PDE4 and the NDE1/NDEL1/LIS1 protein complex via a DISC1 pathway. The data suggested that the PKA phosphorylation of NDE1 modulates the protein binding among NDE1, NDEL1, and LIS1, which is regulated by DISC1-PDE4 interaction. Importantly, the authors specified threonine 131 (T131) of NDE1 as a PKA phosphorylation site and produced a phospho-NDE1-T131 antibody. Thus, the question arising is, What is the effect of the phosphorylation of NDE1 at T131 for brain development? Of interest, the authors observed the accumulation of phosphorylated NDE1 at T131 in the centrosome, spindle pole, and intercellular bridge in mitotic cells, as well as in the post-synaptic density in primary hippocampal neurons. The role for the phosphorylation of NDE1 for neuronal processes, such as cell proliferation, differentiation, and synaptic function, is expected to be studied in vivo.

Another question is whether the phosphorylation of NDE1 at T131...  Read more

View all comments by Atsushi Kamiya

Primary Papers: Deletion of densin-180 results in abnormal behaviors associated with mental illness and reduces mGluR5 and DISC1 in the postsynaptic density fraction.

Comment by:  Anand Gururajan
Submitted 12 January 2012 Posted 19 January 2012

Comment by Anand Gururjan, Rachel Hill, and Maarten van Den Buuse
Reverse-engineering clinical abnormalities in rodents has been a standard approach to creating models of aspects of psychiatric illness, but with the use of genetic knockouts, we have managed to achieve a level of resolution not previously seen using classical drug-induced, lesion-induced, or neurodevelopmental models. Indeed, the use of knockouts in combination with these techniques would, in theory, provide a more accurate model. However, before such combinations are trialed, we would necessarily need to establish the robustness of the knockout model by itself in terms of its construct and face and predictive validity.

As outlined by Carlisle et al. (2011), a model has been created based on clinical findings that genetic variations in the components of the post-synaptic density fraction (PSD) have been linked to several psychiatric disorders. The PSD machinery plays a very important role in regulating signal strength and also selectivity of signals...  Read more

View all comments by Anand Gururajan
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