Northwestern University's Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, USA
* Author for correspondence (e-mail: jakessler{at}northwestern.edu)
Accepted 19 May 2004
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SUMMARY |
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Key words: Neural stem cell, BMP4, Oligodendroglia, ID, Olig, Astrocyte, Mouse
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Introduction |
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BMP signaling exerts different effects on lineage commitment by neural
stem/progenitor cells at different stages of development. Early in mouse
cortical development (E13) BMP signaling promotes neuronal lineage commitment
by cultured neural progenitor cells (Li et
al., 1998; Mabie et al.,
1999
), whereas later in development (E16 and thereafter) it
promotes astrocytic differentiation of ganglion eminence progenitor cells
(Gross et al., 1996
;
Mehler et al., 1995
;
Zhu et al., 1999a
), cortical
progenitor cells (Mabie et al.,
1999
) and O2A progenitor cells
(Grinspan et al., 2000
;
Mabie et al., 1997
). However,
at all stages of development BMP signaling consistently inhibits
oligodendroglial lineage commitment by cultured progenitor cells
(Gross et al., 1996
;
Mehler et al., 1995
;
Zhu et al., 1999a
).
Conversely, treatment of cultured glial progenitors with noggin, an inhibitor
of BMP signaling, promotes oligodendrogenesis
(Mabie et al., 1999
).
Furthermore, transgenic overexpression of BMP4 enhances astrocyte lineage
commitment in vivo and significantly inhibits the generation of OLs
(Gomes et al., 2003
), whereas
overexpression of the BMP inhibitor, noggin, under the same promoter
conversely increases the number of oligodendroglia and inhibits
astrogliogenesis (J.A.K., unpublished).
The molecular mechanisms by which BMPs inhibit oligodendrogenesis are not
known. BMP signaling upregulates expression of the inhibitor of
differentiation (Id) family of proteins
(Miyazono and Miyazawa, 2002)
in diverse cell types such as neuroepithelial cells
(Nakashima et al., 2001
),
osteoblasts (Ogata et al.,
1993
) and embryonic stem cells
(Hollnagel et al., 1999
). The
ID family of proteins includes four related helix-loop-helix transcription
factors (Id1-Id4) which do not contain the basic DNA binding regions
adjacent to the helix-loop-helix dimerization domain
(Norton et al., 1998
). Basic
helix-loop-helix (bHLH) factors can be broadly classified into two groups,
Class A factors and Class B factors. The class A factors, or E proteins (E2-2,
HEB, and the E2A gene products E12 and E47), are expressed ubiquitously and
are able to dimerize with tissue-specific class B bHLH factors to activate
gene expression (Massari and Murre,
2000
). ID proteins sequester the class A factors, inhibiting the
formation of active class A-class B heterodimers and thus act as dominant
negative regulators of differentiation
(Benezra et al., 1990
;
Sun et al., 1991
). However,
the IDs may also bind to some class B bHLH factors involved in muscle
differentiation such as MyoD and Myf-5
(Langlands et al., 1997
).
Cells of the OL lineage express IDs and the bHLH factors OLIG1 and OLIG2
(Lu et al., 2000;
Zhou et al., 2000
). In
Olig1/2 double-mutant mice, there is a complete failure of OL
development in all areas of the brain along with an apparent increase in
astrocytogenesis in the spinal cord (Zhou
and Anderson, 2002
). This indicates that Olig1/2
expression is essential for oligodendrogliogenesis and suggests that
repression of OL development may be sufficient to cause astrogliogenesis.
Expression of Id4 in OL precursor cells progressively decreases as
the precursor cells differentiate in vivo and in vitro
(Kondo and Raff, 2000
).
Overexpression of Id2 inhibits OL differentiation and its absence
induces premature OL differentiation in vitro
(Wang et al., 2001
).
This study shows that ID2 and ID4 directly interact with OLIG1 and OLIG2
while all the ID proteins act to sequester the E2A proteins. Overexpression of
Id4 or Id2 or treatment with BMP4 inhibits OL lineage
commitment even in cells that overexpress Olig1 and Olig2,
and enhances astrogliogenesis. Conversely, inhibition of Id4
expression by RNA interference (RNAi) blocks the inhibitory effects of BMP4 on
OL lineage commitment. These observations suggest that ID4 and ID2
sequestration of OLIG proteins mediates the inhibitory effects of BMP
signaling on OL lineage commitment and underlies the restriction of
oligodendrogliogenesis to ventral regions of the nervous system where Shh
signaling predominates (Orentas and
Miller, 1996; Qi et al.,
2002
; Wada et al.,
2000
).
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Materials and methods |
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Immunocytochemistry
Cells cultured on coverslips were fixed with 4% paraformaldehyde. Mouse
monoclonal antibodies against 2'3' cyclic nucleotide
phosphodiesterase (CNPase) 1:800 (Sternberger Monoclonals), myelin basic
protein (MBP) 1:600 (Sternberger Monoclonals), glial fibrillary acid protein
(GFAP) 1:400 (Sigma), ß-tubulinIII 1:400 (Sigma), anti-chk GFP antibody
1:3000 (Chemicon), NG2 1:400 (Chemicon) and OLIG2 1:500 (UT Southwestern) or
rabbit polyclonal antibodies against OLIG1 1:500 (Chemicon), ID2 and ID4 1:50
(Santa Cruz) were applied overnight at 4°C. Then the appropriate
fluorophore conjugated-secondary antibodies 1:1000 (Molecular Probes) were
applied and the nuclei were counterstained with DAPI. Controls were performed
without primary antibody, with alternate primary antibodies, and with
inappropriate secondary antibodies to show negligible background. Total
cellular counts for each experimental condition were obtained by examining the
entire area of each coverslip from three independent culture wells; the result
for each experimental condition was verified a minimum of three times. For
double staining OLIG1 and IDs, zenon rabbit antibody labeling kit (Molecular
Probes) was used.
Bacterial two-hybrid assay
The manufacturer's protocol in the bacterial two-hybrid kit (Stratagene)
was followed.
Co-immunoprecipitation (Co-IP)
Two hundred and ninety-three cells were co-transfected with pCDNAID1-4 and
pCDNA-OLIG1/2, using Fugene6 transfection reagent (Roche) and Co-IP was
performed according to manufacturer's recommendations in the protein G
immunoprecipitation kit (Roche). Antibodies used for CO-IP were specific
anti-IDs (1:50) (Santa Cruz) and anti-his6 antibody (1:150) (Invitrogen) for
OLIGs. Western analyses of the precipitates were performed for the other
interacting protein using the following antibodies: specific anti-IDs (1:200)
(Santa Cruz), anti-OLIG1 (1:200) (Chemicon), anti-OLIG2 (1:200) (UT
Southwestern) and anti-myc 9E10 supernatant (1:10) (DSHB). For detection of
endogenous protein-protein interactions, E17 EGF-generated neurosphere cells
treated with BMP4 (20 ng/ml) for 12 hours were lysed followed by CO-IP with
anti-OLIG1, specific anti-IDs and normal rabbit IgG (1:50) (Santa Cruz).
Quantitative Real Time Polymerase Chain Reaction (QRT-PCR)
QRT-PCR was performed using Perkin-Elmer's ABI Prism 7700 Sequence Detector
System. Total RNA was extracted from cells using Trizol reagent (Invitrogen).
cDNA was prepared using the thermoscript RT-PCR kit (Invitrogen). QRT-PCR was
performed with an initial denaturation of 10 minutes at 95°C, followed by
40 cycles of 15 seconds' denaturation at 95°C and 1 minute of annealing
and elongation at 60°C. SYBR green 1 dye was used to produce the
fluorescent signal that was detected at the annealing phase. Specificity of
the PCR reaction was confirmed by running PCR products on 2% agarose gel. Two
replicates were run for each cDNA sample with the test and control primers in
separate wells of a 96-well plate. An amplification plot showing cycle number
versus the change in fluorescent intensity was generated by Sequence Detector
program.
RNA interference (RNAi)
Oligonucleotides were designed such that a loop sequence TTCAAGAGA was
placed in-between sense and antisense sequences corresponding to
AAGN18TT in the coding sequence of ID4. The sense and antisense
oligonucleotides with 5' phosphates and PAGE purification were annealed
and cloned into pLentilox 3.7 (gift from Luk Van Parijs). Lentivirus was made
by transfecting HEK293T cells with pLentilox 3.7 plasmid and packaging
plasmids. After the virus was concentrated and titered, 5x105
viral particles were used to infect approximately 105 neural stem
cells. Cells were grown as neurospheres for 48 hours after viral infection and
then dissociated cells were plated on PDL-coated coverslips. Viral titers were
5x106 on average and approximately 80% progenitor cells were
infected. Phenotypic analysis was done after 48 hours.
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Results |
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ID2 and ID4 regulate the fate of neural progenitor cells
To determine whether the IDs might mediate effects of BMP4 on lineage
commitment, we compared effects of lentiviral overexpression of Id2
and Id4 with the effects of treatment with BMP4 in cultured E17
progenitor cells. Levels of overexpressed IDs were confirmed by western blot
analysis (Fig. 3A). Levels of
ID4 appeared to be higher than ID2, although this could simply reflect
differences in the antibodies used for blotting. Forty-eight hours after
infection with the lentivirus, cultures were analyzed by immunofluorescence
for neuronal (ß-tubulinIII), astrocytic (GFAP) and oligodendrocytic
(CNPase and MBP) markers (Fig.
3B). As noted previously, treatment with BMP4 reduced the numbers
of CNPase+ and MBP+ cells by more than 95% and increased
the number of GFAP+ cells by 2.5-fold
(Fig. 3C). Overexpression of
Id2 reduced the number of CNPase+ cells by only
approximately 25% and the number of MBP+ cells by approximately 40%
and increased the number of GFAP+ cells 2.5-fold. However,
overexpression of Id4 resulted in a significant 80% reduction in the
number of CNPase+ cells and almost a 90% reduction in the number of
MBP+ cells while increasing GFAP+ cells approximately
2.5-fold. Combined overexpression of Id2 and Id4 did not
differ significantly from overexpression of Id4 alone, and none of
the treatments significantly altered the number of
ß-tubulinIII+ cells. Overexpression of Id1 or
Id3 did not alter oligodendroglial or astrocytic lineage commitment
(data not shown). These results suggest that Id4 and Id2
could act as downstream effectors of BMP4 in producing the inhibition of
oligodendrogenesis and enhancement of astrocytic lineage commitment.
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Discussion |
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BMP signaling inhibits oligodendrogenesis in vitro and in vivo
BMPs secreted from the roof plate provide dorsalizing signals during
development and inhibit the formation of ventral cell types
(Liem et al., 1997;
Liem et al., 1995
) whereas Shh
produced by the notochord and floor plate provides ventralizing signals
promoting the development of OLs (Orentas
and Miller, 1996
; Poncet et
al., 1996
; Pringle et al.,
1996
; Trousse et al.,
1995
). Several studies have suggested that the development of OL
depends on the balance between the dorsalizing BMP signaling and ventralizing
Shh signaling (Liem et al.,
2000
; Mekki-Dauriac et al.,
2002
; Patten and Placzek,
2002
).
BMP signaling inhibits oligodendrogenesis from cultured progenitor cells
and enhances astrogliogenesis (Gross et
al., 1996; Li et al.,
1998
; Mabie et al.,
1999
; Mabie et al.,
1997
; Mehler et al.,
1995
; Grinspan et al.,
2000
; Zhu et al.,
2000
). Further, overexpression of BMP4 in transgenic mice under
the control of neuron-specific enolase promoter results in a significant
decrease in OL numbers concurrent with an increase in astrocytes
(Gomes et al., 2003
).
Conversely, overexpression of noggin under the control of the same promoter
increases the number of OLs and decreases astrocytes (J.A.K., unpublished).
Finally, ablation of the dorsal spinal cord in chick embryos or inactivation
of BMP signaling by noggin in vivo results in the appearance of OLPs dorsal to
their normal domain (Mekki-Dauriac et al.,
2002
). Taken together, these studies provide strong evidence that
BMP signaling provides the inhibitory signal that restricts the foci of
oligodendrogenesis in vivo. Thus, ventral Shh signaling induces expression of
OL lineage species whereas dorsal BMP signaling inhibits
oligodendrogliogenesis.
ID proteins act as effectors of BMP4 signaling
Which intracellular factors mediate the effects of BMP signaling on lineage
commitment? BMP4 treatment of cultured neural progenitor cells increases
expression of all four ID proteins (Fig.
2). BMPs also induce Id expression in several other cell types,
including osteoblasts (Ogata et al.,
1993) and embryonic stem cells
(Hollnagel et al., 1999
).
Moreover, the Id1 promoter is activated by BMPs in a smad-dependent
manner (Korchynskyi and ten Dijke,
2002
; Lopez-Rovira et al.,
2002
) suggesting that the Ids are direct targets of BMP
signaling (Miyazono and Miyazawa,
2002
). The Id family includes four structurally related proteins
ID1-4 which act as dominant negative antagonists of bHLH transcription factors
in various cell lineages (Benezra et al.,
1990
; Riechmann et al.,
1994
; Sun et al.,
1991
). Each ID protein has a distinct pattern of expression in the
developing nervous system with characteristic spatial and temporal patterns in
restricted cell types. For example, ID1 and ID3 are detected in dividing
neuroblasts, whereas ID2 and ID4 are expressed in relatively mature neurons,
and ID2 and ID3 are absent in O4+ OLs
(Jen et al., 1996
;
Jen et al., 1997
;
Tzeng and de Vellis, 1998
).
This suggests that the cellular specificity of the Id gene family may play a
critical role in lineage commitment. Expression of Id2 and
Id4 declines progressively as OLPs undergo maturation, and
overexpression of Id2 and Id4 in OLPs inhibits OL
differentiation, whereas their absence induces premature differentiation in
vitro (Kondo and Raff, 2000
;
Wang et al., 2001
). Because
ID2 and ID4 levels decline when OLPs are induced to differentiate by
withdrawal of PDGF, it was hypothesized that the Ids enhance the rate of
proliferation and thus inhibit OL differentiation when overexpressed in OLPs
(Kondo and Raff, 2000
;
Wang et al., 2001
). In this
study, we found that overexpressing Id2 and Id4 in cultured
progenitor cells not only inhibits OL fate specification but also increases
astrocytic differentiation (Fig.
3), similar to that observed with BMP4 treatment. Further,
inhibition of Id4 expression reversed the phenotype seen with BMP4
exposure (Fig. 3). Because BMPs
induce the ID proteins, we can conclude that the IDs mediate effects of BMP
signaling on glial lineage commitment.
Molecular mechanism of inhibition of oligodendrogenesis
How does ID expression inhibit oligodendroglial lineage commitment? The IDs
are HLH factors, which lack a DNA binding basic domain. Thus, when they
dimerize with other bHLH transcription factors, they inhibit DNA binding and
prevent transcription of downstream targets
(Christy et al., 1991;
Massari and Murre, 2000
). They
typically produce their effects by binding to the ubiquitously expressed class
A bHLH factors such as E2A, HEB and E2-2 proteins
(Benezra et al., 1990
;
Jogi et al., 2002
;
Sun et al., 1991
). However, we
found that all the ID proteins complexed with E2A proteins but only ID4 and
ID2 inhibited oligodendroglial lineage commitment. This suggested that ID4 and
ID2 must exert their effects by binding to other factors. ID proteins also
bind directly to the tissue-specific class B bHLH factors MyoD and Myf5 that
are involved in muscle differentiation
(Langlands et al., 1997
). This
suggested that the ID4 and ID2 proteins might exert their effects on OL
lineage commitment by binding to other class B bHLH transcription factors.
Olig1 and Olig2 are class B bHLH transcription factors
that are important for oligodendrogenesis
(Lu et al., 2000;
Zhou et al., 2000
) and spinal
motor neuron development (Lu et al.,
2002
; Mizuguchi et al.,
2001
; Novitch et al.,
2001
; Park et al.,
2002
; Zhou and Anderson,
2002
). Olig2 is expressed earlier than Olig1 and
both bHLH factors are detectable in OLPs in the vertebrate CNS
(Zhou et al., 2000
). Ectopic
expression of Olig1 in vivo and in vitro induces the formation of OL
precursors (Lu et al., 2001
;
Lu et al., 2000
), whereas
Olig2 expression in vivo causes ectopic expression of Sox10
(Zhou et al., 2000
). Sox10
contains a DNA binding domain of the high mobility group (HMG) and is
predominantly expressed in OLs in the CNS
(Stolt et al., 2002
). It is
also known to directly bind to and activate the myelin basic protein promoter,
thus suggesting a role in differentiation of OLs. In the spinal cord, the
glial precursor domain defined by the expression of
Pdgfra/Olig1/Olig2 has been mapped to the ventral border of the
Pax6 expression domain but dorsal to the Nkx2.2 domain
(Lu et al., 2000
;
Zhou et al., 2000
). Our
results show that ID4 and ID2 bind to OLIG1 and OLIG2 (Figs
5,
6) and thus inhibit the OLIGs
from binding to DNA. Because OLs do not develop in the absence of OLIG1/2
function (Lu et al., 2002
;
Zhou and Anderson, 2002
),
sequestration of the OLIG proteins by ID4 and ID2 would be expected to inhibit
oligodendrogliogenesis (Fig.
9). We also found that BMP4 treatment resulted in cytoplasmic
rather than nuclear localization of OLIG1 and OLIG2
(Fig. 6A), suggesting that
binding to ID proteins prevented the translocation of OLIG proteins to the
nucleus. ID proteins are expressed in the cytoplasm of progenitor cells even
in the absence of BMP signaling (Figs
2,
6), and BMP4 treatment did not
alter the intracellular localization of the ID proteins. Both western analyses
and quantitative RT-PCR demonstrated large increases in expression of the IDs
in response to BMP4 (Fig. 2),
although the increase in ID proteins after BMP4 treatment was not clearly
demonstrated by non-quantitative immunocytochemistry
(Fig. 6). This suggests that
ID4 and ID2 must reach critical levels in the cytoplasm to effectively bind
and sequester the OLIG proteins, thereby preventing their translocation to the
nucleus. OLPs are known to express the E2A proteins, E12 and E47 as well as
OLIG proteins (Sussman et al.,
2002
), and our results demonstrate that the E2A proteins are
binding partners for the OLIG proteins
(Fig. 7). Because the ID
proteins also bind to E2A proteins, this suggests another mechanism by which
the ID proteins may inhibit OLIG function.
|
It is interesting that overexpression of ID4 promoted astrocyte lineage
commitment analogous to the effects of BMP signalling, whereas
Id4-RNAi inhibited the generation of astrocytes. There are two
possible interpretations of this finding. First, it is possible that ID4
exerts actions that directly foster the generation of astrocytes.
Alternatively, astrogliogenesis may simply be fostered by the inhibition of
commitment to the alternate OL lineage. BMPs and LIF act synergistically to
promote astrocytic differentiation of neural progenitor cells
(Nakashima et al., 1999). They
induce the transcription factors smad1 and STAT3 which form a complex with
p300 in the nucleus, resulting in direct activation of the GFAP promoter.
Olig2 represses the astrocyte-specific GFAP promoter by interacting
with p300 and thereby abolishes the complex between STAT3, smad1 and p300
(Fukuda et al., 2004
). The
dominant negative effects of the ID proteins on OLIG functions would thus
derepress GFAP expression and enhance astrocyte specification as well as
inhibit oligodendroglial lineage commitment (Figs
3,
8). In Olig1/2
double-mutant mice, there is a complete failure of OL development in all areas
of the brain and instead there is a small increase in astrocytogenesis
(Zhou and Anderson, 2002
).
This suggests that repression of OL development may be sufficient to cause
astrogliogenesis, consistent with the findings of Fukuda et al.
(Fukuda et al., 2004
) as well
as our own findings.
In summary, BMP signaling regulates glial lineage commitment by inducing expression of the ID proteins, particularly ID4, which complex with both OLIG proteins and with the E2A proteins which are OLIG binding partners (Fig. 9). This inhibits the generation of OLs in regions where BMP signaling predominates, such as the dorsal spinal cord, and may enhance the generation of astrocytes.
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ACKNOWLEDGMENTS |
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