1 Department of Neurophysiology and Brain Science, Graduate School of Medical
Sciences, Nagoya City University, Mizuhoku, Nagoya 467-8601, Japan
2 Department of Pathology, Niigata Rosai Hospital, Japan Labor Health and
Welfare Organization, 1-7-12 Tooun-cho, Jhoetsu, Niigata 942-8502, Japan
3 Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane
4029 Queensland, Australia
4 Department of Molecular Neurobiology, Graduate School of Medical Sciences,
Nagoya City University, Mizuhoku, Nagoya 467-8601, Japan
Author for correspondence (e-mail:
miura-ngi{at}umin.ac.jp)
Accepted 21 September 2005
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SUMMARY |
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Key words: Cell cycle, Neuron, Differentiation, ATBF1, ATM, Isthmus, Rat
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Introduction |
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Here, we present evidence that ATBF1 plays an essential role in cell cycle arrest and neural differentiation during embryogenesis. ATBF1 is highly expressed in the nucleus of postmitotic cells, resulting in suppression of the nestin gene and activation of the Neurod1 gene (previously NeuroD) for neuronal differentiation. The subcellular localization of ATBF1 is closely correlated with cell proliferation and cell cycle arrest.
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Materials and methods |
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SYBR Green real-time RT-PCR analysis
Total RNAs isolated from whole brains at E12.5, E18.5, P1, P3, P7 and P28
using Trizol (Invitrogen) were reverse-transcribed and a part of each
complementary DNA template was used for SYBR Green real-time PCR.
Amplification was performed with the following primers: Atbf1,
5'-TTC TTT TCC TCC TCT CTC CTC ATC-3' and 5'-CGG TCC GTC GGA
CTT TTG-3'; ß-tubulin III, 5'-AAG GCC TTC CTG CAC TGG
TA-3' and 5'-TCT CGG CCT CGG TGA ACT C-3'; Gfap,
5'-CGC TCA ATG CTG GCT TCA-3' and 5'-AAG CGG TCA TTG AGC TCC
AT-3'; and Gapdh, 5'-TGT GTC CGT CGT GGA TCT GA-3'
and 5'-CCT GCT TCA CCA CCT TCT TGA-3'. The expression of each gene
was normalized by the corresponding amount of Gapdh mRNA. The
relative amounts of each product were calculated by the comparative CT
(2-CT) method described in User Bulletin #2 of the
ABI Prism 7000 Sequence Detection System (Applied Biosystems).
Cell cultures
Neuroepithelial cells from the ganglionic eminence (GE) of E14.5 rats were
mechanically dispersed and cultured in serum-free DMEM/F12 (1:1) supplemented
with N-2 supplements (GIBCO) and 10 ng/ml FGF2 (Pepro Tech EC) for the
induction of neurospheres. Neuro 2A mouse neuroblastoma cells were maintained
in minimum essential medium (MEM) containing 10% fetal bovine serum. P19 mouse
embryonal carcinoma cells were maintained in -MEM containing 10% fetal
bovine serum. To induce neuronal differentiation, P19 cells were aggregated on
bacterial grade dishes for 4 days with 0.5 µM all-trans RA (Sigma) and then
transferred to tissue culture dishes without RA
(Rudnicki and McBurney, 1987
).
Cells were replated on glass slides coated with combinations of
poly-L-ornithine (Sigma), fibronectin (Invitrogen), laminin (Invitrogen),
poly-L-lysine (Sigma) and gelatin (Sigma) for immunostaining.
Transfections and constructs
The Atbf1 expression vectors consists of an 11 kb of full-length
human cDNA (Miura et al.,
1995) inserted in the pCI vector (Promega) with an HA-tag or
Myc-tag sequence at the 5'-terminal of the inserted sequence
(Nojiri et al., 2004
). The
mouse Neurod1 (BETA2)-luciferase reporter plasmid was kindly
provided by Prof. M.-J. Tsai (Huang et al.,
2000
). The nestin enhancer fragment was a gift from Prof. H. Okano
(Kawaguchi et al., 2001
). The
promoter fragments were subcloned into the pGV-B basic luciferase reporter
plasmid (Promega). An internal control vector, pRL-TK (Promega) was
co-transfected to normalize the efficiency of transfection and the cells were
analyzed by the dual-luciferase assay system (Promega). Typically, 1 µg of
DNA was transfected with TransIT (Mirus) in 24-well dishes for 3 hours in the
presence of 10 ng/ml FGF2, after which the cells received fresh medium.
FACS analysis
Cultured cells were washed three times with PBS, and then stained in 50
µg/ml propidium iodide (Sigma-Aldrich), 0.1% sodium citrate, 20 µg/ml
ribonuclease A and 0.3% IGEPAL CA-630 (Sigma-Aldrich). In total,
1x104 cells were analyzed using a flow cytometer (FACScan;
Becton Dickinson) to determine the cell cycle phases.
Pharmacological reagents
Leptomycin B (LMB, 20 nM; Sigma), wortmannin (100 nM; Calbiochem),
ryanodine (10 nM-100 µM; Sigma) and caffeine (1-20 mM; Sigma) were applied
30 minutes before changing the culture conditions during the treatment with RA
(0.5 µM; Sigma).
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Results |
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The GE is an ideal region for investigating neuronal differentiation in the context of cell cycle regulation, because the process of neural differentiation can be clearly observed as separate layers composed of proliferating cells or fully differentiated neurons. BrdU-labeled cells were limited to the ventricular zone (VZ) and subventricular zone (SVZ), and absent from the differentiating field (DF) and white matter (W) (Fig. 1C1,C2). Nestin, a neural stem cell marker, was expressed in the VZ and SVZ (Fig. 1D1,D2). ATBF1 expression in the nucleus was mainly seen in the DF, and co-expressed with ß-tubulin III (Fig. 1E1,E2). Most of the microtubule-associated protein 2 (MAP2)-positive cells also expressed ATBF1 (64±9%, n=1505) (Fig. 1F1,F2). ATBF1 expression in the GE was higher at earlier stages (E12.5 and E14.5) and decreased dramatically at a later stage (E18.5) (not shown).
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Overexpression of ATBF1 induces cell cycle arrest
In a mouse neuroblastoma cell line, Neuro 2A cells, BrdU uptake was stopped
once Atbf1 was transfected (Fig.
3B1-B5). The amount of cells in the G1/G0 phase was 33% (M1 in
Fig. 3E1,E3) after transfection
of a mock vector and this increased to 77% (M1 in
Fig. 3E2,E4) after the
transfection of the ATBF1 expression vector. There was no remarkable change in
the number of apoptotic cells after transfection of the ATBF1 expression
vector (2.9±0.2%, n=1127)
(Fig. 3D1-D5) compared with
that after transfection of a mock vector (3.0±0.8%, n=1310)
(Fig. 3C1-C5).
Nuclear localization of ATBF1 is associated with cell cycle arrest
In a mouse embryonal carcinoma cell line, P19 cells, the cell cycle was
maintained in the floating condition (Fig.
4A1) and embryonic bodies were formed at a high density of the
cells (Fig. 4B1-B4), even
though ATBF1 expression was elevated by 50-fold within 24 hours of RA
treatment owing to induction of neuronal differentiation
(Miura et al., 1995). ATBF1
was expressed in the cytoplasm of P19 cells in the floating condition, but
became localized in the nucleus after the cells were separated from the
embryonic bodies and became attached to the culture plate
(Fig. 4C1-C4). FACS analysis
revealed that the population in the G1/G0 phase was low when ATBF1 was present
at a low level (Fig. 4A,
M1=42%) or expressed in the cytoplasm in the embryonic bodies
(Fig. 4B, M1=54%), and
increased when ATBF1 was localized in the nucleus in adherent cultures
(Fig. 4C, M1=83%), resulting in
neuronal differentiation.
Isolation from cell-to-cell interaction induces nuclear localization of ATBF1
Next, we examined the mechanism that controls the subcellular localization
of ATBF1. Once the cells attached to coated surfaces ATBF1 became localized in
the nucleus (Fig. 5A1-A5). We
searched for the intracellular signaling pathway that induces the nuclear
localization of ATBF1. As phosphatidylinositol-3-kinase [PI(3)K]-related
pathways are involved in regulating the major trafficking processes of various
nuclear factors for cell growth (Seoane et
al., 2004) and neural differentiation
(Hermanson et al., 2002
;
Peng et al., 2004
), the effect
of ATBF1 may also be related to PI(3)K-mediated signaling. To investigate such
an involvement, we used inhibitors of PI(3)K family enzymes, namely LY294002
and caffeine (Sarkaria et al.,
1999
), during the neuronal differentiation process of P19 cells.
After pre-treatment with LY294002 for 30 minutes, the nuclear localization of
ATBF1 was partially inhibited and showed a mosaic appearance
(Fig. 5A6). The effect of
ryanodine treatment (100 µM) was weak and showed partial inhibition of the
nuclear localization of ATBF1 (Fig.
5A7). Pre-treatment with caffeine (5 mM) for 30 minutes induced
distinct inhibition of the nuclear localization of ATBF1
(Fig. 5A8). Under the floating
aggregated condition, ATBF1 was expressed in the cytoplasm
(Fig. 5B1), but treatment with
LMB (Nishi et al., 1994
), an
inhibitor of CRM1 (Kudo et al.,
1997
), increased the concentration of ATBF1 in the nucleus
(Fig. 5B2). ATBF1 was
immediately localized in the nucleus after treatment with EDTA (1 mM, 30
minutes) and a pipette that caused mechanical dissociation into single cells
(Fig. 5B3).
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Nuclear localization of ATBF1 in the differentiating field of embryonic brain
The density of cells should alter the interaction of cell-to-cell and
cell-to-extracellular matrix (ECM). Intracellular signaling is likely to
respond differentially to cell-to-cell and cell-to-ECM interactions via
adhesion molecules on cell surface. At the GE of the embryonic brain, ATBF1
was localized in the cytoplasm at the VZ
(Fig. 7A,A1) and strongly
expressed in the nucleus at the DF (Fig.
7A,A3). The expression of fibronectin
(Fig. 7B), one of the
constituent factors of the ECM, was sparse and cells were congested at a high
density in the VZ (Fig. 7B,B1),
while the ECM was dense with a lower density of cells in the DF (Fig. 8B,B3).
We observed a similar phenomenon regarding the density of cells and the
subcellular localization of ATBF1 at the isthmus
(Fig. 7C,C1).
Pregnant rats were administered BrdU for 3 hours to label E14.5 embryos. The cells expressing ATBF1 in their cytoplasm (Fig. 7E,E1) were detected by BrdU incorporation indicating proliferation (Fig. 7D,D1) in the layer facing the ventricle with higher density of cells (Fig. 7C,7C1, region I); by contrast, those expressing ATBF1 in their nucleus (Fig. 7E and E2) were arrested in the postmitotic phase without detection of BrdU (Fig. 7D,D2) in the outer layer facing the ECM with lower density of cells (Fig. 7C,C1, region II).
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Discussion |
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ATBF1 was expressed in the postmitotic cells in association with
ß-tubulin III and MAP2, both markers of neuronal differentiation. ATBF1
expression was associated with the suppression of nestin during neuronal
development. The nestin gene is regulated by interplay of SOX and POU factors
in neural primordial cells (Tanaka et al.,
2004). The suppressive effect of ATBF1 against the nestin-specific
element may be due to competitive inhibition between POU factors and ATBF1,
which also harbors a POU domain in its structure
(Morinaga et al., 1991
). The
function of ATBF1 in suppressing nestin and promoting neuronal differentiation
appears to be opposite to that of the nuclear receptor co-repressor (N-CoR),
which maintains the proliferation of nestin-positive neuronal stem cells
(Hermanson et al., 2002
). The
translocation of N-CoR from the nucleus to the cytoplasm was observed as the
`on' switch of neuronal differentiation and the `off' switch of nestin
expression (Hermanson et al.,
2002
). Once ATBF1 localizes in the nucleus, it is likely to form
complexes with nuclear receptors via its leucine-rich helix motif (2275,
LSMLL), which may result in the dissociation of N-CoR
(Perissi et al., 2004
;
Perissi et al., 1999
). The
function of ATBF1 in activating the Neurod1 promoter in the nucleus
is consistent with the function of Neurod1 as a key transcription factor that
induces neuronal differentiation by activating Trkb and
p21CipI/KipI promoters
(Liu et al., 2004
). ATBF1
might activate Neurod1 expression in cooperation with other co-factors known
to regulate the promoter element of the Neurod1 gene. The
Neurod1 gene promoter is regulated by complex formation with the bHLH
transcription factor neurogenin (Ngn1), Smad1 and CBP/p300
(Sun et al., 2001
). PIAS3 is a
factor that forms co-activator complexes with Smads and p300/CBP for various
target genes (Long et al.,
2004
). We have previously revealed a strong interaction between
ATBF1 and PIAS3 by co-immunoprecipitation experiments
(Nojiri et al., 2004
). Taken
together, these studies suggest that ATBF1 in association with PIAS3, Smads
and p300/CBP may play an important role in the activation of the
Neurod1 promoter.
|
ATBF1 contains three leucine-rich domains, which are potential nuclear
export signals (NESs) (Fornerod et al.,
1997) (1267, LQLHLTHL; 2471, LPQLVSLPSL, 2504, LSHLPLKPL).
Treatment of p19 cells with LMB resulted in nuclear localization of ATBF1,
indicating that CRM1 (Nishi et al.,
1994
) may be involved in this process. The primary translocation
of ATBF1 from the cytoplasm to the nucleus may be driven by the potential
nuclear localization signals (NLSs) (277, KRKPILMCFLCK; 1387, KRPQLPVSDRHVYK;
2947, KRFRTQMTNLQLK; 2987, KRVVQVWFQNARAKEKKSK)
(Gorlich et al., 1994
;
Imamoto et al., 1995
;
Moroianu et al., 1995
;
Pollard et al., 1996
) in
ATBF1.
|
|
ATBF1 is specifically expressed until the postnatal stage in the nucleus of
dopaminergic neurons (Ishii et al.,
2003) that are selectively affected in ATM-deficient mice
(Eilam et al., 1998
). ATBF1
contains 28 potential Ser-Gln/Thr-Gln (SQ/TQ) cluster domains that may be a
direct substrate for PI(3)K-related activity of ATM
(Rotman and Shiloh, 1998
).
Absence or dysfunction of the ATM protein causes ataxia-telangiectasia (AT), a
human disease that shows remarkable elevation of AFP expression
(Chun and Gatti, 2004
). The
elevation of AFP may be explained by the dysfunction of ATBF1, as ATBF1 is the
major suppressive factor for Afp gene transcription
(Morinaga et al., 1991
;
Yasuda et al., 1994
). These
observations suggest that the expression of ATM, a member of the PI(3)K
superfamily, is highly correlated with the function of ATBF1 as a gene
regulatory factor in the nucleus.
|
Since caffeine has another effect through the activation of ryanodine receptors on the endoplasmic reticulum in the cytoplasm, we examined the possible involvement of this signaling pathway. In contrast to caffeine, ryanodine treatment weakly inhibited the translocation of ATBF1 from the cytoplasm to the nucleus. Thus, the results of the present study suggest partial involvement of ryanodine-induced Ca2+ signaling in regulating the subcellular localization of ATBF1, although the distinct effect of caffeine of keeping ATBF1 out of the nucleus is primarily associated with the PI(3)K activity of ATM in the nucleus. Thus, the signaling through the 28 SQ/TQ ATM target sites on ATBF1 that may regulate the nuclear localization of ATBF1 remains to be understood.
In this report, we have elucidated that the subcellular localization of ATBF1 has a remarkable functional meaning linking to cell proliferation versus cell cycle arrest. The alteration of signaling from the cell-to-cell to cell-to-matrix interactions triggered the nuclear localization of ATBF1. Overexpression studies supported the view that ATBF1 is one of the important factors in the nucleus that coordinates the cellular differentiation associated with the cell cycle arrest.
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ACKNOWLEDGMENTS |
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Footnotes |
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