A Review of Disrupted-in-Schizophrenia-1 (disc1):

Neurodevelopment, Cognition, and Mental Conditions

Koko Ishizuka, Matt Paek, Atsushi Kamiya, and Akira Sawa
Disrupted-In-Schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic
biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive
functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-
Schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications.
Disrupted-In-Schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule
fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that
DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both
cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or
dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically
engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and
starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed.

Key Words: DISC1, schizophrenia, neurodevelopment, knockout further confirmation by other genetic analyses, such as linkage
mice, transgenic mice and association studies, to conclude that the DISC1 gene is
directly implicated in major mental illnesses.
Finnish groups have reported a positive linkage at the DISC1

D
isrupted-In-Schizophrenia-1 (DISC1) is a promising can-
didate gene for schizophrenia (SZ) and bipolar disorder
(BP), but its basic biology remains to be elucidated.
Accumulating genetic evidence supports that DISC1 is associated
with some aspects of cognitive functions relevant to SZ and BP.
Identification of DISC1 and Genetic Support as a
Promising Candidate Gene for Schizophrenia
Millar et al (2000) originally reported on two genes disrupted
in a hereditary balanced chromosome (1;11) (q42.1; q14.3)
translocation that segregated with SZ and related psychiatric
disorders, including schizoaffective disorder, bipolar disorder
(Blackwood et al 2001), and recurrent major depression. The
majority of the family members with the translocation, and none
without the translocation, have one of these diagnoses. The
disrupted genes at the chromosomal breakpoint 1q42.1 were
named DISC1 and Disrupted-In-Schizophrenia-2 (DISC2). Dis-
rupted-In-Schizophrenia-1 is the only disrupted gene that has an
open reading frame or protein coding potential. Disrupted-In-
Schizophrenia-2 occurs on the opposite strand to that of DISC1
and is apparently an untranslated gene that has no definitive
function. As an antisense transcript, DISC2 may modulate DISC1
expression. There is little evidence for the presence of any
transcripts within the sequence surrounding the breakpoint on
chromosome 11 (Millar et al 2000). However, there may be still
slight possibilities that some genes on chromosome 11 are
affected by the translocation.
The linkage of the chromosomal abnormality and familial
psychosis in the Scottish pedigree may be due to the disruption
of DISC1 (and/or DISC2), but positional effects due to the
chromosomal translocation may not be excluded. Thus, we await
From the Departments of Psychiatry and Behavioral Sciences (KI, MP, AK, AS)
and Neuroscience (AS), Johns Hopkins University School of Medicine,
Baltimore, Maryland.
Address reprint requests to Akira Sawa, M.D., Ph.D., Johns Hopkins Univer-
sity School of Medicine, Department of Psychiatry, CMSC 8-117 N Wolfe
Street, Baltimore, MD 21287; E-mail: asawa1@jhmi.edu.
Received July 27, 2005; revised December 8, 2005; revised March 28, 2006;
accepted April 10, 2006
locus with two independent sample sets for SZ (Ekelund et al
2001, 2004). In a linkage study of 52 Taiwanese families with at
least two affected SZ siblings, D1S251, located near the DISC1
gene had a maximal nonparametric linkage (NPL) score of 1.73
(Hwu et al 2003). Linkage of the DISC1 locus in BP has also been
reported (Curtis et al 2003; Detera-Wadleigh et al 1999; Macgre-
gor et al 2004; McInnis et al 2003). Of most interest, Hamshere et
al (2005) recently reported that the highest linkage peak (LOD
3.54) occurs at 1q42, close to the DISC1 locus in a genome-wide
linkage scan in schizoaffective disorder. These linkage results
suggest that DISC1 may have a role as a common susceptibility
factor for both SZ and mood disorders.
Genetic association studies also support that DISC1 may play
a role in major mental illnesses and associated cognitive func-
tions (Burdick et al 2005; Callicott et al 2005; Cannon et al. 2005;
Hennah et al 2003, 2005; Hodgkinson et al 2004; Thomson et al
2005; Zhang et al 2006). A common haplotype, HEP3, which
contains two single nucleotide polymorphisms (SNPs) (T-A allele
at rs751229 and rs3738401) is undertransmitted to SZ in Finnish
and is also associated with poor visual working memory and
attention (Hennah et al 2003, 2005). In a large Scottish case-
control study, the C-A allele combination of the SNPs of HEP3 is
strongly associated with SZ (Zhang et al 2006). Another common
haplotype, HEP1, consisting of three SNPs (rs6675821,
rs1000731, and rs3890280) is overrepresented among individuals
with SZ in a Finnish population-based twin cohort study. In this
study, HEP1 is also associated with impaired long-term verbal
memory and total hippocampal volume reduction (Cannon et al
2005). A case-control study of a North American white popula-
tion showed that the Hap3 haplotype, which was corresponding
to HEP1, was associated with schizoaffective disorder (Hodgkin-
son et al 2004). A rare haplotype of combined HEP2/HEP3
segment incorporating four SNPs (rs1615409, rs766288, rs751229,
and rs3738401) was overrepresented in SZ with an association
with impaired spatial working memory, increased reaction time
to visual targets, and reduced prefrontal gray matter (Cannon et
al 2005).
Overrepresentation of a missense allele in exon 9 of the
DISC1 gene (Leu607Phe) was reported in patients with schizo-
affective disorder (Hodgkinson et al 2004). The Ser allele of

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doi:10.1016/j.biopsych.2006.03.065 2006 Society of Biological Psychiatry
1190 BIOL PSYCHIATRY 2006;59:1189 1197 K. Ishizuka et al

Table 1. Comparison Among Schizophrenia Susceptibility Genes

Gene Locus Linkage Association Cytogenetics Biological Function Mouse Model

DISC1 1q42 b b a Neuronal migration (Kamiya et al 2005) PPI deficit in tg mice with
mutDISC1e (Hikida et al,
unpublished data, 2005; Li et al,
unpublished data, 2005; Xu et al,
unpublished data, 2005)
Synaptic organization (Kirkpatrick et al in Impairment of working memory in
press) mice with a DISC1 deletion
variant (Koike et al 2006)d
cAMP signal transduction (Millar et al
2005)
NRG1 8p12-21 a a c Neuronal migration (Anton et al 1997; Rio PPI deficit in NRG1/ mice
(Neuregulin1) et al 1997) (Stefansson et al 2002)d
Neurotransmission (Ozaki et al 1997;
Stefansson et al 2002)
Myelination (Traveggia et al 2005;
Vartanian et al 1999)
DTNBP1 6p22 a a c Vesicular trafficking (Li et al 2003) No PPI deficit in dysbindin null mice
(Dysbindin1) (Sandy) (Li et al 2003)d
Synaptic plasticity (Talbot et al 2004) Abnormal behaviors upon
pharmacological challenges in
Sandy mice (Srivastava et al)f
Neurotransmission (Numakawa et al 2004;
Talbot et al 2004)
DISC1, Disrupted-In-Schizophrenia-1; cAMP, cyclic adenosine monophosphate; NRG1, Neuregulin1; DTNBP1, Dysbindin1; PPI, prepulse inhibition; tg,
transgenic.
a
Very strong.
b
Strong.
c
Not available.
d
Published.
e
Meeting abstracts.
f
Personal communication.

another nonsynonymous single nucleotide polymorphism in
exon 11 (Ser704Cys) was reportedly associated with SZ and
reduction in hippocampal gray matter volume and N-acetylas-
partate (NAA) signals, as well as abnormal engagement of the
hippocampus during several cognitive tasks assessed with func-
tional magnetic resonance imaging (fMRI) (Callicott et al 2005).
In a large Scottish cohort study, the Cys allele at this SNP was
associated with stronger cognitive decline in aged women com-
pared with aged men (Thomson et al 2005). Negative association
of DISC1 and SZ has also been reported, most notably in
case-control studies in Japanese populations, suggesting a pos-
sible effect of ethnic backgrounds (Devon et al 2001; Kockelkorn
et al 2004; Zhang et al 2005).
In an American pedigree, a 4-base pair (bp) deletion at the
extreme 3 end of exon 12 of DISC1 was reported in a SZ
proband, a sibling with SZ, a sibling with schizoaffective
disorder, and the unaffected father, whereas the mutation was
not detected in 424 control individuals (Sachs et al 2005). The
mutation is predicted to cause a frameshift and encode a
truncated protein with nine abnormal C-terminal amino acids.
The truncated transcript is detectable, but at a reduced level,
in lymphoblastoid cell lines from three of four mutation
carriers.
Taken together, these lines of genetic evidence have rein-
forced the concept that DISC1 is a promising susceptibility gene
for SZ, compatible to neuregulin-1 and dysbindin (Table 1). From
the standpoint of bridging genetic information to biological
studies, DISC1 is uniquely advantageous. Disrupted-In-Schizo-
phrenia-1 has genetic variations associated with the disease that
lead to potential changes at the protein level, which can greatly
expand the breadth of the studies (Callicott et al 2005; Hodgkin-
son et al 2004; Millar et al 2000; Sachs et al 2005).
DISC1: Multiple Isoforms at Messenger RNA and Protein
Levels
The DISC1 gene has at least 13 exons with an open reading
frame that can encode a protein consisting of 854 amino acids
(Millar et al 2000, 2001) (Figure 1). The Scottish translocation
occurs between exons 8 and 9, interrupting the coding sequence
of the DISC1 gene, which could lead to loss of the C-terminal 257
amino acids of the protein.
DISC1 Expression at the Messenger RNA Level
Northern blotting indicates that DISC1 transcript(s) occur
mainly in the brain, heart, placenta, testis, and kidney (Ma et al
2002; Millar et al 2000). The precise expression of DISC1
transcript(s) in brains was addressed by in situ hybridization.
Disrupted-In-Schizophrenia-1 is expressed in adult mouse
brains, with highest levels in the dentate gyrus of the hippocam-
pus and lower expression in CA1CA3 of the hippocampus,
cerebral cortex, olfactory bulb, and cerebellum (Austin et al 2004;
Ma et al 2002). Expression of DISC1 in the limbic regions,
especially the dentate gyrus of the hippocampus, is observed in
adult primate brains (Austin et al 2003).
Splicing of DISC1 messenger RNA (mRNA) is complex (Figure
1). In humans, at least four different DISC1 transcripts have been
reported that are referred to as L (long), Lv (long variant), S

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K. Ishizuka et al BIOL PSYCHIATRY 2006;59:1189 1197 1191

Human
breakpoint
1 23 4 5 6 78 9 10 1112 13
1b 9a

ATG A B Stop
L
[James et al 2004] Figure 1. Exon/intron structure of DISC1 gene. The
Lv [Taylor et al 2003] DISC1 gene has 13 major and several minor exons.
mRNA
(Est) Several EST clones have been published (L, Lv, S, and
S Es). In addition, monkey has an isoform that skips exon
4. Several groups have generated anti-DISC1 antibod-
Es ies, and their epitopes (corresponding exons or a por-
tion of exons) are depicted. DISC1, Disrupted-In-
Schizophrenia-1; EST, expressed sequence tag; L, long;
[Ozeki et al 2003] Lv, long variant; S, short; Es, extremely short.
[Sawamura et al 2005]
C1 C2
R1211
Abs R47 [James et al 2004 ]
S602 R1443/1
D26 [Brandon et al 2004]
D27
[Miyoshi et al 2003]
Rat Human
DISC1 DISC1

(short), and Es (extremely short) (Taylor et al 2003). The L form
is encoded by all 13 exons, and the Lv form differs from the L
form through the utilization of a splice donor site with exon 11
(indicated in Figure 1 as the A donor site for the Lv, in contrast to
the B donor site for the L). The S form splices from exon 9 to an
alternate exon between exons 9 and 10, referred as exon 9a,
which leads to an in-frame stop after one codon in exon 9a. The
Es form does not utilize the splice donor site of exon 3, instead
extending the exon 3 open reading frame for two codons before
an in-frame stop codon. There is an additional exon between
exons 1 and 2 (exon 1b) that allows an alternative translational
initiation in the same frame as that for the L transcript (Ozeki et
al 2003).
DISC1 Expression at the Protein Level
Reflecting the complexity of DISC1 expression at the mRNA
level, a variety of DISC1 protein signals have been reported by
Western blotting (Brandon et al 2004; James et al 2004; Miyoshi et al
2003; Ozeki et al 2003; Sawamura et al 2005; Schurov et al 2004).
Thus far, at least four groups have reported on antibodies
against several portions of DISC1 (Figure 1). The DISC1 signal at
100 105 kDa has been reproducibly reported in several studies
(Table 2). Thus, the signal at 100 105 kDa may reflect the entire
translated product from the DISC1 open reading frame (854
amino acids). Some antibodies detect signals that occur more
prominently in the developing cerebral cortex, especially with
those that are slightly larger than 100 105 kDa. Since DISC1 may

Table 2. Summary of DISC1 Antibodies Generated in the Previous Studies

Species Materials Antibodies DISC1 Bands (kDa) References

Brains
Human Orbitofrontal cortex C2 7085, 95100 Sawamura et al 2005
Rat Adult cerebellum R1211 75, 100, 150 James et al 2004
Postnatal Rat DISC1 78, 105 Miyoshi et al 2003
Mouse Adult D27 75, 100 Brandon et al 2004
Fetal, postnatal, adult D27 71, 75, 100, 105 Schurov et al 2004
Fetal, adult C1 80, 95, 105, 120, 130 (Figure 2)
Fetal, adult C2 7080, 90, 105, 120 (Figure 2)
Cells
Human SH-SY5Y C2 7085 Sawamura et al 2005
R47 71, n-75, 80, 98, 100, 150, 200 James et al 2004
S602 71, n-75, 98, 150 James et al 2004
R1443/1 c-75, 100, 150, 200 James et al 2004
D26 95, 130 Brandon et al 2004
SK-N-SH Human DISC1 78, 105 Miyoshi et al 2003
HEK293T Human DISC1 78, 105 Miyoshi et al 2003
HEK293 R47 80 James et al 2004
HeLa C2 7085 Sawamura et al 2005
Lymphoblasts C2 75 Ozeki et al 2003
Rat PC 12 Rat DISC1 78, 105 Miyoshi et al 2003
C2 75, 100 Ozeki et al 2003
DISC1, Disrupted-In-Schizophrenia-1.

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1192 BIOL PSYCHIATRY 2006;59:1189 1197
be a phosphoprotein (Morris et al 2003), the larger signals may
be the full-length DISC1 with posttranslational modifications
specifically occurring during neurodevelopment. The DISC1-
associated bands that are larger than the above signals in
Western blotting have also been interpreted as traces of a
putative DISC1 protein dimer or a protein complex including
DISC1. Clearly, it will be important to determine temporal and
spatial regulation of posttranslational modifications of DISC1.
In addition to the DISC1 signals between 100 130 kDa, there
are signals that are smaller than 100 kDa (Brandon et al 2004;
James et al 2004; Miyoshi et al 2003; Ozeki et al 2003; Sawamura
et al 2005; Schurov et al 2004). Thus, signal(s) at 70 85 kDa
detected by the C2 antibody have been assessed by mass
spectrometry, which indicates that the signal(s) reflect a form of
DISC1 containing the amino acids in exons 2 and 5 (Sawamura et
al 2005). However, the signal(s) have not yet been fully charac-
terized. Furthermore, antibodies against distinct portions of
DISC1 recognize different small DISC1 variants. Correlation of
the known isoforms of DISC1 mRNA to many bands in the
Western blotting remains to be elucidated. Systematic generation
of antibodies against different portions of DISC1 would be a
possible approach to characterize its small variants.
Several studies have addressed spatial and temporal regula-
tion of DISC1 protein expression in brains (Brandon et al 2004;
Miyoshi et al 2003; Ozeki et al 2003; Schurov et al 2004). Most of
the studies indicate that DISC1 expression occurs preferentially
in the forebrain (hippocampus, cerebral cortex, and olfactory
bulbs) from embryonic to adult stages, which is consistent with
DISC1 expression at the mRNA level. Expression of DISC1 is
regulated developmentally with the highest expression in the
cerebral cortex of rodent brains during late embryonic days
(Ozeki et al 2003). Another study reports additional peaks of
protein expression of a DISC1 isoform at embryonic day 13.5
(E13.5) and postnatal day 35 (P35) when active neurogenesis
occurs in mouse brains (Schurov et al 2004). As far as we are
aware, three studies have addressed DISC1 expression in brains
by using immunohistochemistry. One study suggests neuronal
expression of DISC1, especially in granule cells in the dentate
gyrus, as well as pyramidal neurons within the CA1CA3 regions
of hippocampus (James et al 2004). Schurov et al (2004) used an
excellent antibody against DISC1 (D27) and demonstrated its
expression in neurons of the cortex, hippocampus, hypothala-
mus, cerebellum, and the brain stem. Disrupted-In-Schizophre-
nia-1 expression is remarkable in layers II/III and V/VI in the
cerebral cortex, in CA3 of the hippocampus, and in Purkinje cells
of the cerebellum. The most recent study also confirms expres-
sion of DISC1 in neurons of the cerebral cortex (Kirkpatrick et al,
in press).
Subcellular distribution of DISC1 has been analyzed in both
neuronal and nonneuronal cells (Brandon et al 2004; James et al
2004; Miyoshi et al 2004; Morris et al 2003; Ozeki et al 2003;
Sawamura et al 2005). In addition, Kirkpatrick et al (in press)
examined the distribution by immunoelectron microscopy (im-
muno-EM) with autopsied human brains from normal control
subjects. At this time, at least four major subcellular domains
have been reported. First, DISC1 occurs in the microtubule-
associated cytoskeletons and the centrosome that functions as
the microtubule organizing center in cells (Brandon et al 2004;
Miyoshi et al 2004; Morris et al 2003; Ozeki et al 2003). Second,
DISC1 immunostaining is co-localized with indicators for mito-
chondria in HeLa cells and primary neurons (Brandon et al 2005;
James et al 2004; Ozeki et al 2003). This staining may reflect
microtubule-associated cargoes for mitochondria, because the
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K. Ishizuka et al
(1) (2) (3) (4)
exo
(kDa) DISC1 Mouse Mouse Human
-HA F A F A A
FL?
98
64
HA C1 C2 C2
Figure 2. Multiple isoforms of DISC1 protein. Western blotting for DISC1
with several antibodies is shown. (1) HEK293 cell extracts overexpressing
HA-tagged human full-length DISC1 protein is probed with an anti-HA
antibody. A single band at 105 kDa is observed. (2) Mouse brain extracts
probed with an anti-DISC1 antibody (C1: against 350 600 amino acids)
(Ozeki et al 2003). In addition to the signal at 105 kDa, additional signals at
80, 95, 120, and 130 kDa are observed. F, fetal brains at E18; A, adult brains at
3 months. (3) Mouse brain extracts probed with an anti-DISC1 antibody (C2;
against 600 854 amino acids) (Ozeki et al 2003). In addition to the signal at
105 kDa, signals at 70 80, 90, and 120 kDa are observed. (4) Human adult
brain extracts. Signals at 70 80 and 95 kDa are observed. Gray arrows:
signals commonly observed more than one independent antibody. Red
arrows: signals only obtained with C1. Blue arrows: signals only obtained
with C2. Blue asterisk: the signal that was confirmed as an isoform of DISC1
by mass spectrometry (Sawamura et al 2005). Tris-glycine gels at 8% were
used for the Western blotting in this figure to obtain higher resolution in the
range between 100 and 140 kDa, compared with previous publications.
DISC1, Disrupted-In-Schizophrenia-1; HA, high affinity.
DISC1 staining similar to that of mitochondria is dramatically
changed by treatment with the microtubule depolymerizing
agents, including nocodazole (Brandon et al 2005). Third, DISC1
immunostaining is most prominently enriched in the postsynap-
tic density (PSD) of adult brains in immuno-EM studies (Kirk-
patrick et al, in press). Fourth, immuno-EM studies on adult
brains indicate nuclear localization of a pool of DISC1 (Kirk-
patrick et al, in press). Interestingly, significant changes in
subcellular distribution of a DISC1 small variant at 70 85 kDa
occur in brains from patients with SZ and those with major
depression (Sawamura et al 2005). Substance abuse and alcohol
abuse, but not smoking, also contribute to the alteration.
Representative blots with two antibodies against DISC1 (C1
and C2) are shown to demonstrate complexity of DISC isoforms
with developmental changes (Figure 2).
In summary, DISC1 has multiple isoforms with potential
posttranslational modification. Its expression seems to be regu-
lated temporally and spatially. Further information on DISC1
expression should provide insight into the regulation of these
processes in cell and animal models for DISC1.
DISC1: Multiple Subcellular Distributions and Cellular
Functions
Disrupted-In-Schizophrenia-1 was identified as a novel pro-
tein of unknown function that is predicted to consist of an
N-terminal head domain and a long helical tail domain (Millar et
al 2000) (Figure 3). The tail domain contains several stretches of
amino acids that have the potential to form coiled-coil domains.
Nevertheless, these amino acid sequences cannot provide
enough information to predict any specific functions.
To explore possible functions of DISC1, several groups have
conducted yeast two-hybrid screening, a genetic method to
identify protein interactors (Lyons-Warren et al 2005; Millar et al
2003; Miyoshi et al 2003, 2004; Morris et al 2003; Ozeki et al
K. Ishizuka et al
Synaptic
spines
DISC1
Citron
DISC1
Microtubules
DISC1
Mitochondria
DISC1 NUDEL
LIS1
DISC1
Nucleus Centrosome
PDE4B
ATF 4
DISC1
2003). The DISC1-interacting proteins in yeast two-hybrid
screenings can be divided into at least three or four groups: 1)
microtubule-associated, especially centrosome-associated pro-
teins, including NudE-like (NUDEL), NUDE, dynactin, kendrin,
microtubule-interacting protein associated with TRAF3 (MIPT3),
and microtubule-associated protein 1A (MAP1A); 2) possible
nuclear proteins that include activating transcription factor 4
(ATF4); 3) actin-associated proteins such as spectrin, -actinin2,
and fasciculation and elongation protein zeta-1 (FEZ 1); and 4)
postsynaptic density (PSD)-associated proteins that are involved
in synaptic morphology and plasticity, such as Citron and
huntingtin-associated protein interacting protein (HAPIP). Be-
cause actin cytoskeletons play an important role in regulating
cytoskeletal organization of the postsynaptic regions, the pro-
teins classified in groups 3 and 4 above may be functionally
related. Of note, the classification of DISC1 interactors in this
manner (microtubules/centrosome, actin/synapse, and nucleus)
is correlated with the observations of DISC1 subcellular distribu-
tion described above (microtubules/centrosome, mitochondria,
synapse, and nucleus).
Recently, phosphodiesterase 4B (PDE4B) was reported to
bind to DISC1, and its protein interaction might play a regulatory
role in cyclic adenosine monophosphate (cAMP) signaling (Mil-
lar et al 2005). Because PDE4B is substantially enriched in the
mitochondria, this may account for a role of mitochondrial
DISC1. Alternately, mitochondria-associated staining of DISC1
can be explained by proposing that DISC1 participates in micro-
tubule-associated cargoes for mitochondria.
To address possible functions of DISC1 more directly, cell
models with overexpression of exogenous DISC1 have been
utilized. Transient expression of the C-terminal truncated mutant
DISC1 (mutDISC1) that corresponds to disruption in the Scottish
pedigree inhibits neurite outgrowth (Ozeki et al 2003). In
contrast, stable transfection of full-length DISC1 in PC12 cells
enhances neurite outgrowth when the cells are differentiated in
the presence of nerve growth factor (Miyoshi et al 2003). RNA
interference (RNAi) to knock down endogenous DISC1 has also
BIOL PSYCHIATRY 2006;59:1189 1197 1193
Actin
FEZ1 Cytoskeleton
Figure 3. Multiple subcellular distribution of DISC1
protein. Disrupted-In-Schizophrenia-1 shows multi-
ple subcellular distributions, including the centro-
some and microtubule fractions, the postsynaptic
densities, the actin cytoskeletal fractions, the mito-
chondria, and the nucleus. Disrupted-In-Schizophre-
nia-1 protein interactors have been explored with a
variety of techniques. Thus far, several potential
DISC1 interactors in relevant subcellular fractions to
DISC1 are being intensively studied, including LIS1,
NUDEL, Citron, FEZ1, PDE4B, and ATF4. DISC1, Dis-
rupted-In-Schizophrenia-1; LIS1, Lissencephaly 1;
NUDEL, NudE-like; FEZ1, fasciculation and elongation
protein zeta-1; PDE4B, phosphodiesterase 4B; ATF4,
activating transcription factor 4.
been used in cell models. Application of RNAi to differentiating
PC12 cells and primary hippocampal neurons leads to inhibition
of neurite outgrowth (Kamiya et al 2005; Taya et al, unpublished
data, 2005). Three distinct, but potentially interacting, mecha-
nisms have been suggested to account for how DISC1 facilitates
neurite outgrowth. Disrupted-In-Schizophrenia-1 at the centro-
some associated with the dynein/microtubule motors, including
NUDEL and LIS1, may modulate microtubular dynamics that
results in neurite outgrowth in cells (Kamiya et al 2005; Ozeki et
al 2003). Disrupted-In-Schizophrenia-1 can also form a protein
complex with NUDEL/LIS1/14-3-3epsilon together with Kine-
sin-1, which can facilitate outgrowth (Taya et al, unpublished
data, 2005). Interaction of FEZ-1 and DISC1 also facilitates
outgrowth, but this may be more associated with actin cytoskel-
etal mechanisms (Miyoshi et al 2003). In each scenario, this
cellular phenotype suggests a potential role for DISC1 in neuro-
development in vivo, including neuronal migration and neuronal
network formation, which can be addressed in animal models.
A recent biochemical study suggests that interaction of DISC1
and NUDEL could inhibit oligopeptidase activity, an alternative
activity, of NUDEL (Hayashi et al 2005). No study has addressed
the potential roles of DISC1 in synapses and the nucleus, which
would be of interest to pursue in association with the interacting
proteins of DISC1, such as Citron and activating transcription
factor 4 (ATF4), respectively.
Self-Association of DISC1 Protein, a Dominant-Negative
Function of C-Terminal Truncated Mutants
As described above, genetic variants of DISC1 are known to
be associated with major mental illnesses (Callicott et al 2005;
Hodgkinson et al 2004; Millar et al 2000; Sachs et al 2005) (Figure
4). These changes result in 1) the Scottish mutation due to a
balanced chromosomal translocation (Millar et al 2000); 2) a
frameshift mutation that could result in a C-terminal truncated
protein with nine abnormal C-terminal amino acids (Sachs et al
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1194 BIOL PSYCHIATRY 2006;59:1189 1197
Scottish Frameshift
breakpoint site
wt DISC1
Scottish SZ
mutDISC1 Dominant negative
degraded
mut2-DISC1
? ?
General SZ? x x
Self association NUDEL
domain Binding domain
Ser704Cys
Leu607Phe
2005); 3) Ser704Cys polymorphism (Callicott et al 2005); and 4)
Leu607Phe polymorphism (Hodgkinson et al 2004) .
Among them, the Scottish mutation due to the chromosomal
translocation displays the clearest segregation between the dis-
eases and the mutation, although the penetrance is not perfect
(majority of family members with the chromosomal abnormality
are diagnosed with major mental illnesses, but none of other
family members without the abnormality has the diseases)
(Blackwood et al 2001). The impact of the chromosomal abnor-
mality is still unclear. Because there is almost no coding potential
in the fused regions from chromosome 11 due to the balanced
translocation (Millar et al 2000), it is unlikely that there is a
significant addition of amino acids to the truncated DISC1. In
contrast, the Scottish C-terminal truncated DISC1 that is coded in
chromosome 1 (mutDISC1) may acquire a unique function, such
as a gain of function or dominant-negative function. The loss of
the C-terminal region of DISC1 due to the chromosomal abnor-
mality may simply lead to some deficiency (loss of function).
Alternatively, the deletion of the C-terminal region itself may lead
to instability of the protein. In lymphoblasts of a few individuals
with SZ from the Scottish pedigree, mutDISC1 protein could not
be detected (Millar et al 2005). This may be partly because there
are differences in the metabolism of DISC1 protein between the
developing brain and lymphoblasts (Sawa and Snyder 2005).
Biochemical and cellular approaches have revealed, at least in
part, the mechanism by which mutDISC1 affects cellular func-
tions (Kamiya et al 2005; Ozeki et al 2003; Taya et al, unpub-
lished data, 2005). Disrupted-In-Schizophrenia-1 forms a protein
homodimer or homo-oligomer via the self-association domain in
the middle portion of the protein that is still present in mutDISC1.
As a result, expression of mutDISC1 that contains this domain
leads to misdistribution of exogenous wild-type (full-length)
DISC1, but expression of mutDISC1 that lacks the self-association
domain does not. Expression of mutDISC1 in COS cells detaches
endogenous DISC1 at the centrosome, which further results in
detachment of other protein components of the dynein complex,
such as LIS1 and dynactin, from the centrosome. Thus, as
indicated above, a pool of DISC1 has a role in maintaining the
dynein protein complex at the centrosome (Kamiya et al 2005).
All the patients in the Scottish family have one intact and one
mutant chromosome (Blackwood et al 2001). Mutated DISC1 fails
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K. Ishizuka et al
Figure
. 4. Schematic representation of DISC1 variants
at the protein levels. The chromosomal abnormality in
the Scottish family (Millar et al 2000) could lead to
production of the C-terminal truncated mutant DISC1
(mutDISC1) (in orange). In cell and animal models, mut-
DISC1 shows a dominant-negative function. Because
LOSS OF of protein instability, mutDISC1 may be easily de-
FUNCTION
graded. In either scenario, the Scottish chromosomal
abnormality may lead to loss of DISC1 function. A
frameshift mutation found in the American pedigree
(Sachs et al 2005) could result in a C-terminal truncated
protein with nine abnormal C-terminal amino acids (in
scarlet; the additional nine amino acids are depicted in
pink). In nonfamilial cases, genetic polymorphisms
that lead to missense mutations at amino acids at 607
and 704 are indicated. Self-association domain, NUDEL
binding domain, location of the Scottish breakpoint,
and the frameshift site are depicted. DISC1, Disrupted-
In-Schizophrenia-1; mutDISC1, mutant DISC1; NUDEL,
NudE-like
to locate to the centrosome, because loss of the DISC1 C-terminal
domain leads to failure to form the protein complex that contains
LIS1, dynein, and NUDEL. Simultaneously, mutDISC1 interferes
with the function of wild-type DISC1 of maintaining the dynein
protein complex at the centrosome in a dominant-negative
fashion. Taken together, mutDISC1 may lead to overall loss of
DISC1 function associated with the dynein protein complex at
the centrosome (Kamiya et al 2005). Haploinsufficiency of DISC1
due to the protein instability of mutDISC1 is also suggested by
David Porteouss group (Millar et al 2005), as an alternative
possibility. This idea is also consistent with the concept of overall
loss of function of DISC1 associated with major mental illnesses.
From this standpoint, the frameshift mutation of DISC1 found
in an American pedigree is important (Sachs et al 2005). The
mutation leads to loss of exon 13, where the domain required for
NUDEL binding is coded. An important question is whether or
not the exon 13 deficient DISC1 displays a similar loss of function
and dominant negative effects. No study has addressed how the
polymorphisms at Ser704Cys and Leu607Phe affect cellular func-
tions.
Production of DISC1 Animal Models
Molecular functional analyses of DISC1 in cell models have
revealed its potential role in cytoskeletal organization, especially
during neurodevelopment, and cAMP signaling (Kamiya et al
2005; Millar et al 2005; Miyoshi et al 2003; Ozeki et al 2003; Sawa
and Kamiya 2003; Taya et al, unpublished data, 2005). These
studies also suggest that overall loss of DISC1 function may be
implicated in the pathophysiology of major mental illnesses
(Kamiya et al 2005; Millar et al 2005; Sawa and Snyder 2005). As
described above, it is advantageous in designing genetically
engineered mice that DISC1 has genetic variations associated
with the disease. Thus, several groups are starting to generate
and examine DISC1 genetically engineered mice as models for
studying major mental illnesses.
Production of DISC1 Knockout Mice
Generation of DISC1 knockout mice should provide the most
straightforward way to dissect the functions of DISC1 in vivo.
There are, however, potential risks in generating DISC1 knock-
K. Ishizuka et al
out mice. These include the possibility of alternative uses of
exons, including those that contain translation initiation sites.
There are several DISC1 isoforms that have not been fully
characterized (Brandon et al 2004; James et al 2004; Miyoshi et al
2003; Ozeki et al 2003; Sawamura et al 2005; Schurov et al 2004).
Therefore, depending on which exons are knocked out, alterna-
tive isoforms of DISC1 may compensate for functions of DISC1.
Another major risk in generating the mice is lethality during
development. If DISC1 is essential for neurodevelopment and
embryonic survival, it is possible that knockout animals may not
be obtained because of abnormal neurodevelopment. In this
case, conditional knockout mice utilizing the Cre/loxP system
may be considered (Pluck 1996).
Production of Transgenic Mice Expressing DISC1, Especially
mutDISC1
It is still controversial whether or not mutDISC1 is expressed
in brains. Analysis of mutDISC1 in cell models, however, sug-
gests that regardless of its expression, the Scottish chromosomal
abnormalities may lead to an overall loss of DISC1 function and
that cells and animals expressing mutDISC1 would be useful as
model systems to test its dominant-negative effects, that is, the
outcome of knocking down DISC1 functions.
The choice of promoter that drives the transgene is important
in making appropriate transgenic mice. Disrupted-In-Schizo-
phrenia-1 is expressed mainly in the forebrain and is prominent
during neurodevelopment (Austin et al 2003, 2004; Ma et al 2002;
Ozeki et al 2003). It is still unclear whether or not DISC1
expression is restricted to neurons. Moreover, we still do not
know whether DISC1 occurs in interneurons that play an impor-
tant role in the pathology of SZ (Lewis et al 2005). Thus, currently
no transgenic mice can be the ideal animal models for DISC1;
instead, comparison of more than one type of DISC1 transgenic
mice generated under different promoters will be informative. As
far as we are aware from meeting presentations, three groups,
including our group, have successfully generated DISC1 trans-
genic mice (Li et al, unpublished data, 2005; Hikida et al,
unpublished data, 2005; Xu et al, unpublished data, 2005).
Our group has generated two types of DISC1 transgenic mice
with two distinct promoters, the Ca2/calmodulin-dependent
protein kinase II (CaMKII) and prion protein (PrP) promoters.
The limitation of using the CaMKII promoter is that this drives the
transgene only after the late stage of neurodevelopment in
pyramidal cells of the cerebral cortex and hippocampus, al-
though this pattern is consistent with preferential expression of
DISC1 in the forebrain. In contrast, the PrP promoter is better in
driving transgenes during earlier neurodevelopment but is less
advantageous in driving transgenes in various types of cells in
brains. So far, we have performed a neuroanatomical assessment
with magnetic resonance imaging (MRI) and behavioral assays of
mutDISC1 transgenic mice under the CaMKII promoter. Our
studies have shown enlargement of lateral ventricles, deficit in
prepulse inhibition, modest hyperactivity, and impaired olfactory
function (Hikida et al, unpublished data, 2005).
Li, Silva, and colleagues (unpublished data, 2005) have gen-
erated DISC1 transgenic mice using a tamoxifen inducible sys-
tem. In their system, a variety of mutant DISC1 proteins were
fused to a variant of estrogen receptor ligand-binding domain
(LBD) that is specifically activated by the ligand tamoxifen. The
CaMKII promoter regulates the expression of LBD-DISC1 gene.
The induction of a mutant DISC1 fragment at postnatal day 7
produced SZ-like behavioral deficits in the adult animals such as
BIOL PSYCHIATRY 2006;59:1189 1197 1195
impaired sociability, abnormal latent inhibition, and poor spatial
working memory.
Pletnikovs lab in collaboration with our lab has generated a
transgenic model of inducible forebrain-restricted expression of
mutDISC1 using a system using tetracycline (Xu et al, unpub-
lished data, 2005). Compared with control littermates, both male
and female transgenic mice had comparable body size and
weight but exhibited a number of behavioral alterations, includ-
ing decreased habituation of the acoustic startle, locomotor
hyperactivity in the open field, and abnormal spatial learning and
memory in Morris water maze.
In Utero Gene Transfer of RNAi or Expression Constructs
Instead of generating transgenic or knockout mice, gene
transfer into developing embryos by electroporation has been
widely used to analyze the functions of genes that play roles
during neurodevelopment (Bai et al 2003; Shu et al 2004; Tabata
and Nakajima 2001; Xie et al 2003). Both expression constructs
and RNAi constructs can be transfected by this method. The
introduced constructs are incorporated into progenitor cells for
neurons near the ventricular zones (Tabata and Nakajima 2001).
By using this method, we introduced RNAi constructs to DISC1,
as well as an expression construct for mutDISC1.
By knocking down gene expression of DISC1, our lab has
recently obtained evidence that DISC1 is required for proper
neuronal migration of the cerebral cortex during development in
vivo (Kamiya et al 2005). Disturbance of DISC1 during neurode-
velopment finally results in subtle dendritic abnormalities after
the completion of delayed migration, which appears to resemble
the pathology found in brains from patients with SZ. The extent
of these anatomical changes is correlated with the levels of
knock down expression of DISC1. Of interest, introduction of
mutDISC1 also leads to these anatomical changes. These results
suggest that mutDISC1 may function as a dominant-negative in
developing cerebral cortex, which is consistent with the obser-
vations in cell models. The results obtained from the experiments
with in utero gene transfer should be an important reference in
generating and characterizing DISC1 knockout and transgenic
mice in the near future.
Mice with Spontaneous Mutation of DISC1 in the 129S6/SvEv
Strain
Recently, a deletion variant in the DISC1 gene specific to the
129S6/SvEv strain was reported (Koike et al 2006). This mutation
introduced a termination codon at exon 7, abolished production
of the full-length protein, and impaired working memory perfor-
mance when transferred to the C57BL/6J genetic background.
This mouse is not genetically engineered but provides insights
into how DISC1 variation contributes to SZ susceptibility.
Conclusions
Disrupted-In-Schizophrenia-1 seems to be a protein with
multiple functions, but accumulating evidence has suggested that
DISC1 has a role in neurodevelopment and cellular signaling.
This fits with a concept that SZ is a disorder of neurodevelop-
ment (Lewis and Levitt 2002; Raedler et al 1998). Furthermore, SZ
occurs as a result of interaction between genetic and environ-
mental factors (Sawa et al 2004; Sawa and Snyder 2002). To
explore mechanisms of such interactions, DISC1 genetically
engineered mice may be useful tools. Effects of viral infection or
complications during prenatal and neonatal development to-
gether with DISC1 can be examined in mice overexpressing or
knocking down DISC1 that are exposed to those environmental
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1196 BIOL PSYCHIATRY 2006;59:1189 1197
factors in vivo. It would be interesting to test how such genetic
and environmental effects during neurodevelopment give rise to
anatomical and behavioral alterations later in adults, and it also
would be worthwhile to test how neurotransmission, especially
dopaminergic and glutamatergic, is altered in DISC1 mice. Cross-
breeding of DISC1 mice to the mice with another susceptibility
factor for major mental illnesses being engineered, such as
neuregulin-1 knockout mice (Stefansson et al 2002), may also be
used to test synergistic effects of genetic risk factors for major
mental illnesses.
The present work is supported by U.S. Public Heath Service
Grant MH-069853 and foundation grants from National Alli-
ance for Research on Schizophrenia and Depression (NARSAD),
Stanley as well as S-R.
We appreciate Dr. Pamela Talalay for critical reading of this
manuscript. We thank Ms. Yukiko Y. Lema for organizing the
figures and manuscript.
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