Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA
* Author for correspondence (e-mail: b.appel{at}vanderbilt.edu)
Accepted 1 May 2003
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SUMMARY |
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Key words: Delta, Notch, Oligodendrocytes, Motoneurons, Neural precursors, CNS, Spinal cord, Zebrafish
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INTRODUCTION |
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Several lines of evidence have now raised the possibility that Notch
signaling directly promotes development of some types of glial cells. First,
formation of Müller glia in the retina was promoted by forced expression
of Notchac and by overexpression of Hes1 and Hes5, which are
downstream components of the Notch signaling pathway
(Furukawa et al., 2000;
Hojo et al., 2000
;
Scheer et al., 2001
). Second,
in utero retroviral infection of the telencephelon of mouse embryos showed
that Notchac could promote the formation of radial glia, which gave
rise, postnatally, to astrocytes (Gaiano
et al., 2000
; Chambers et al.,
2001
). Third, in cells of the peripheral nervous system,
activation of Notch signaling induced the formation of Schwann cells from
purified neural crest stem cells (Morrison
et al., 2000
) and permitted glial development while blocking
neurogenesis, in cultured quail neural crest cells
(Wakamatsu et al., 2000
). The
manner in which Notch promotes glial development is unknown, although, in
dorsal root ganglia, the asymmetric distribution of Numb proteins might
influence Delta-Notch mediated decisions for neuronal or glial fate
(Wakamatsu et al., 2000
).
Until recently, most work investigating the role of Notch signaling in
development of oligodendrocytes, the myelinating glial cell type of the CNS,
focused on control of oligodendrocyte differentiation. When immature
oligodendrocyte progenitor cells (OPCs) purified from rat optic nerve were
exposed to Notch ligands, they did not differentiate, in contrast to control
experiments (Wang et al.,
1998). Consistent with this observation, selective inactivation of
Notch1 in OPCs in vivo caused their premature differentiation
(Genoud et al., 2002
) and
oligodendrocytes became myelinated too soon in mice heterozygous for a
Notch1 mutation (Givogri et al.,
2002
). Additionally, astrocytes in demyelinating lesions of human
multiple sclerosis patients upregulated Jagged1, a Notch ligand, and Jagged1
blocked maturation of purified human OPCs
(John et al., 2002
). These
observations provide strong evidence that Notch signaling inhibits
differentiation of cells once they enter the oligodendrocyte developmental
pathway. Less clear is whether Notch signaling also promotes specification of
OPCs from neural precursors. Neurospheres from delta-like 1 mutant
mice produced a deficit of OPCs and, conversely, addition of a soluble Notch
ligand to wild-type neurospheres enhanced their formation
(Grandbarbe et al., 2003
).
However, multipotent adult hippocampus-derived progenitors produced fewer
oligodendrocytes when they were transfected with Notchac
(Tanigaki et al., 2001
),
although the markers used in this study did not distinguish between the
possibilities that Notch activity blocked specification or subsequent
differentiation. When electroporated into chick spinal cords,
Notchac could promote formation of OPCs only when co-expressed with
Olig2, a basic helix-loop-helix (bHLH) transcription factor necessary for
oligodendrocyte development (Zhou et al.,
2001
).
Here, we provide in vivo, genetic evidence that Delta-Notch signaling is required for spinal cord oligodendrocyte specification. Spinal cord precursors of mutant zebrafish embryos that had reduced Notch signaling activity stopped dividing prematurely and developed as early-born neurons at the expense of later-born oligodendrocytes. By contrast, transgenic embryos in which Notchac was driven by a conditional expression system had a deficit of neurons and concomitant increase of OPCs. However, formation of OPCs in response to Notchac was restricted to their normal time and place of development. We also show that, subsequent to OPC specification, Notchac blocked oligodendrocyte differentiation, consistent with previous in vitro data. Our data indicate that Notch signaling is important throughout development of oligodendrocytes by promoting specification of OPCs from neural precursors and regulating their subsequent differentiation into mature oligodendrocytes.
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MATERIALS AND METHODS |
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Labeling methods and photomicroscopy
Manually dechorionated embryos were labeled with BrdU by incubating them
for 20 minutes on ice in a solution of 10 mM BrdU and 15% DMSO in embryo
medium (15 mM NaCl, 0.5 mM KCl, 1 mM CaCl2, 1 mM MgSO4,
0.15 mM KH2PO4, 0.05 mM NH2PO4,
0.7 mM NaHCO3). The BrdU solution was replaced with embryo medium
and embryos were incubated for 20 minutes at 28.5°C. The embryos were then
anesthetized using 3-aminobenzoic acid ethyl ester, fixed in 4%
paraformaldehyde, embedded in 1.5% agar/5% sucrose and frozen in
2-methyl-butane chilled by immersion in liquid nitrogen. Sections (10 µm)
were obtained by using a cryostat microtome. Sections were treated with 2 N
HCl for 1 hout, washed with PBS, blocked in PBS plus 2% sheep serum and 2 mg
ml-1 bovine serum albumen (BSA) and then incubated with anti-BrdU
antibody.
Previously described RNA probes included sox10
(Dutton et al., 2001),
ngn1 (Blader et al.,
1997
), tlxa (Andermann
and Weinberg, 2001
), olig2 and plp1/dm20
(Park et al., 2002
). In situ
RNA hybridization was performed as described previously
(Hauptmann and Gerster, 2000
).
Embryos for sectioning were treated as described above. Flat mounted embryos
were dissected from the yolk and mounted in 75% glycerol.
For immunohistochemistry, we used the following primary antibodies: mouse anti-BrdU [G3G4, 1:1000, Developmental Studies Hybridoma Bank (DSHB), Iowa City, Iowa, USA], mouse anti-HuC/D (1:20, Molecular Probes, Eugene, Oregon, USA), rabbit anti-phospho-histone-H3 (1:1000, Upstate Biotechnology, Charlottesville, Virginia, USA). For fluorescent detection of antibody labeling, we used Alexa Fluor 568 goat anti-mouse conjugate (1:200, Molecular Probes) and Alexa Fluor 488 goat anti-rabbit conjugate (1:200, Molecular Probes). Hoechst labeling was performed by incubating sections in Hoechst for 10 minutes following immunolabeling.
In situ hybridization and Hoechst/immunofluorescence images were obtained using a Spot digital camera mounted on a compound microscope. All other fluorescence images were obtained using a Zeiss LSM510 Meta laser scanning confocal microscope. All images were imported into Adobe Photoshop. Image manipulation was limited to levels, curves, hue and saturation adjustments.
Heat shock experiments
Heat shock was applied to transgenic and control embryos in embryo medium
for 30 minutes at 40°C to induce Notch1aac expression.
Following heat shock, embryos were incubated at 28.5°C. Heat-shocked,
transgenic embryos were identified by phenotype, which consisted of touch
insensitivity, abnormal brain morphology and indistinct somites. We confirmed
our identification by labeling a subset of embryos with anti-Myc antibody,
which detects the Myc epitope fused to Notch1aac
(Scheer et al., 2001). To
analyse the number of spinal cord olig2+ and
sox10+ cells, we counted cells in 20 transverse sections
from each of five nontransgenic and five transgenic embryos. Statistical
significance was determined using Student's t test.
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RESULTS |
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Delta-Notch signaling regulates olig2 and ngn1
expression differently
A combinatorial code of bHLH proteins might specify pMN precursors for
motoneuron or oligodendrocyte fates, whereby cells that express Olig2 and Ngns
develop as motoneurons and those that express only Olig2 develop as
oligodendrocytes (Zhou and Anderson,
2002). Thus, we examined expression of zebrafish olig2
and ngn1 to gain further insight into the basis of the mutant
phenotypes described above. In 24 hpf wild-type embryos, a discrete group of
ventral spinal cord cells uniformly expressed olig2
(Fig. 2A) (Park et al., 2002
). By
contrast, ngn1 was expressed in a mosaic throughout the dorsoventral
spinal cord axis (Fig. 2B). Double RNA in situ hybridization showed that a subset of
olig2+ cells expressed ngn1
(Fig. 2C). These expression
patterns are consistent with immunolocalization of Olig2 and Ngn2 proteins in
bird and rodent embryos (Mizuguchi et al.,
2001
; Novitch et al.,
2001
; Zhou et al.,
2001
; Zhou and Anderson,
2002
) and consistent with the idea that motoneurons develop from
olig2+, ngn1+ cells, whereas
oligodendrocytes arise from olig2+,
ngn1- cells.
|
Excess neural plate cells of Notch signaling deficient zebrafish embryos
expressed ngn1, consistent with the excess primary neuron phenotype
of the same embryos (Appel et al.,
2001). Similarly, at 12 hpf, when olig2 expression was
absent from the anterior neural keel, the density of ngn1+
cells was greater in dla-/-;dld-/-
embryos than in wild-type (Fig.
2F,G). Taken together, these data indicate that Delta-Notch
signaling creates a combinatorial bHLH protein code by inhibiting
ngn1 expression and maintaining olig2 expression.
Notch signaling promotes OPC specification and inhibits
oligodendrocyte differentiation
One interpretation of our data is that the requirement for Notch signaling
in formation of spinal cord oligodendrocytes indirectly arises from the
well-known role of Notch signaling in maintaining neural precursor
populations. In this view, Notch signaling prevents neuronal differentiation
of a subset of precursors, which then might be specified for oligodendrocyte
development by another, instructive signal. An alternative, but not mutually
exclusive, possibility is that Notch signaling actively promotes specification
of spinal cord oligodendrocytes. To test this possibility, we used a
transgenic GAL4/UAS system controlled by a heat-shock promoter to drive
ubiquitous expression of a constitutively active form of zebrafish Notch1a
(Notch1aac). Previous studies showed that Notch1aac
expressed in this way persisted for at least 17 hours, effectively blocked
neurogenesis and promoted formation of Müller glia in the retina
(Scheer et al., 2001;
Scheer et al., 2002
).
We first established that heat induction of Notch1aac expression inhibits the formation of spinal cord neurons during embryonic periods relevant to OPC specification. When we induced Notch1aac expression repeatedly at 10, 24 and 36 hpf, to ensure a high level of Notch1aac expression, we found that transgenic embryos lacked most spinal cord neurons, marked by Hu immunofluorescence, at 48 hpf (Fig. 3). Labeling to detect the Myc epitope fused to Notch1aac confirmed that cells strongly expressed Notch1aac at 48 hpf (H.-C. Park, unpublished). Those neurons present in heat-shocked embryos probably were born before Notch1aac accumulated to high level. Consistent with this, when we induced Notch1aac at mid-gastrulation (8 hpf), no spinal cord neurons were present at 24 hpf (H.-C. Park, unpublished). Thus, prolonged Notch1aac expression effectively inhibits spinal cord neurogenesis.
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DISCUSSION |
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Delta-Notch signaling is required for OPC specification
Because mouse embryos that are homozygous for null mutations of
Delta or Notch genes die at early stages of neural
development, there are few data that address the requirement of Notch
signaling for vertebrate CNS glial specification. Recently, this limitation
was circumvented through analysis of mice in which Notch1 was
conditionally inactivated in the cerebellum. These mice prematurely expressed
neuronal markers and had reduced number of mutant cerebellar cells that
expressed the glial marker GFAP (Lutolf et
al., 2002). In an alternative approach, neurospheres were derived
from Delta-like 1 mutant mice. After culturing, mutant neurospheres
produced excess neurons and a deficit of oligodendrocytes and astrocytes
compared with controls (Grandbarbe et al.,
2003
). Additionally, retinas of mice that were homozygous for a
mutation of Hes5, which encodes a downstream effector of Notch
signaling, had fewer Müller glia than the wild type
(Hojo et al., 2000
). These
observations are consistent with the idea that Delta-Notch signaling regulates
neuronal-glial fate decisions.
Several lines of evidence point toward a role for Delta-Notch signaling in
regulating specification of motoneuron and oligodendrocyte fates in zebrafish.
First, prospective primary motoneurons were usually replaced when they were
removed at the 11-somite stage (Appel et
al., 2001) but not at the 13-somite stage
(Eisen et al., 1989
). This is
similar to observations that ablated neuroblasts were replaced by neighboring
cells in grasshoppers (Doe and Goodman,
1985
) and raised the possibility that primary motoneurons, like
grasshopper neuroblasts, inhibit neighboring precursors from adopting the same
fate. Second, prospective primary motoneurons expressed higher levels of
dla and dld than neighboring cells
(Appel and Eisen, 1998
;
Haddon et al., 1998
),
indicating that Notch ligands are present at the right time and place to
regulate specification of cells that arise in close proximity to primary
motoneurons. Third, mutant zebrafish that had reduced levels of Notch
signaling had excess primary motoneurons and a concomitant deficit of
later-born secondary motoneurons, showing that Delta-Notch signaling regulates
specification of neural precursors for different neuronal fates
(Appel et al., 2001
). Finally,
medial neural plate cells, which occupy ventral spinal cord upon completion of
neurulation, gave rise to primary motoneurons and oligodendrocytes
(Park et al., 2002
). Thus,
Delta proteins expressed by primary motoneurons could regulate specification
of nearby cells for oligodendrocyte fate.
Here, we showed that dla-/-;dld-/- and mib-/- embryos did not produce OPCs or premyelinating oligodendrocytes. Additionally, neural precursors prematurely exited the cell cycle and differentiated as neurons in these embryos. As secondary motoneurons and oligodendrocytes arise after primary motoneurons, one interpretation of our data is that Notch signaling prevents a subset of ventral spinal cord precursors from developing as primary motoneurons, enabling them to take later neuronal or oligodendrocyte fates. In this view, downregulation of delta gene expression during primary motoneuron differentiation would result in a decrease of Notch activity in neighboring precursors. A release from Notch-mediated inhibition soon after primary motoneuron specification might allow a cell to develop as a secondary motoneuron, whereas a later release might result in oligodendrocyte development (Fig. 7). Thus, temporal regulation of Notch signaling might underlie the temporal switch in production of primary motoneurons to secondary motoneurons to oligodendrocytes.
|
Our data provide evidence supporting the importance of a bHLH protein code to motoneuron and oligodendrocyte specification and show that Delta-Notch signaling is required to establish the code. We have shown that the failure to restrict ngn1 expression to a subset of medial neural plate cells in Notch signaling deficient zebrafish embryos correlated with formation of excess neurons, consistent with other observations that Notch signaling inhibits proneural genes expression and neuronal development in vertebrate and invertebrate embryos. Furthermore, dla-/-;dld-/- and mib-/- embryos failed to maintain a proliferative population of olig2+ cells. We interpret this to mean that, in the absence of Delta-Notch mediated inhibition, uniformly high levels of Ngns cause all olig2+ neural precursors to stop dividing and differentiate as neurons at the expense of oligodendrocytes. Thus, in normal embryos, high levels of Notch activity prevents ngn gene expression in a subset of olig2+ neural precursors, reserving them to produce other cell types, such as oligodendrocytes, at a later time. In this view, Delta-Notch signaling might play a purely permissive role in neural cell fate diversification, by regulating the ability of neural precursors to respond to other instructive signals.
Delta-Notch signaling promotes oligodendrocyte specification
Another possibility we sought to test is that Notch activity might specify
neural precursors for oligodendrocyte fate. Although several reports already
addressed this possibility, the data are ambiguous. For example, Notch
activity blocked formation of oligodendrocytes from cultured adult
hippocampus-derived progenitors (AHPs)
(Tanigaki et al., 2001).
However, this study assessed oligodendrocyte development using only markers
that reveal late stages of oligodendrocyte differentiation. Because Notch
activity inhibits oligodendrocyte differentiation (see below), OPCs might have
been produced from AHPs but not detected in these experiments. In a different
cell culture assay, Notch activity promoted formation of both OPCs and
astrocytes, apparently from common precursors, within neurospheres
(Grandbarbe et al., 2003
).
However, there are no data that support the presence of a common precursor of
oligodendrocytes and astrocytes in vivo, leaving open the question of whether
Notch signaling specifies OPCs during development. Finally, expression of
constitutively active Notch, alone, by electroporation was not sufficient to
promote OPC formation in chick spinal cords
(Zhou et al., 2001
).
Here, we used a transgenic, conditional expression system to drive high levels of Notch1aac in intact zebrafish embryos throughout the period of neurogenesis. These embryos did not prematurely nor ectopically express OPC markers. However, they had an approximately twofold excess of olig2+ and sox10+ ventral spinal cord cells at 36 and 52 hpf, respectively. By contrast, spinal cord cells of dla-/-;dld-/- and mib-/- embryos initiated but did not maintain olig2 expression and never expressed sox10. Because Notch1aac simultaneously blocked neuronal development, we interpret our results to mean that Notch diverts precursors that would otherwise develop as ventral spinal cord neurons toward an oligodendrocyte fate (Fig. 7). In contrast to canonical models of Notch signaling, which suggest that Notch activity must be downregulated for precursor cells to enter a developmental pathway, our work shows that continuous Notch activity causes ventral spinal cord precursors to develop as oligodendrocytes instead of neurons.
Our observation that Notch1aac expression promoted formation of
excess OPCs only in ventral spinal cord at the normal time of OPC
specification indicates that Notch must act with other spatially and
temporally regulated factors. One candidate is Olig2, as co-electroporation of
plasmids that encode Olig2 and constitutively active Notch promoted ectopic
OPC development in chick embryos (Zhou et
al., 2001). However, in zebrafish, OPCs do not appear to be
specified for at least 36 hours after initiation of olig2 expression.
The Notch pathway must be active in a subset of these cells throughout the
period of olig2 expression to block motoneuron development. This
raises the possibility that the factor that controls the timing of
oligodendrocyte specification is downstream of olig2.
One important problem our data do not address is the nature of motoneuron
and oligodendrocyte precursors. At one extreme, pMN precursors might be
multipotent, having equivalent potential to develop as primary motoneurons,
secondary motoneurons or oligodendrocytes. At the other extreme, pMN
precursors might be restricted to a single fate. A third alternative is that
some precursors produce primary and secondary motoneurons whereas others
produce only oligodendrocytes. Lineage analysis performed in chick embryos
showed that motoneurons and oligodendrocytes can share a precursor but left
unresolved the question of when these cell types become separated in the
lineage (Leber et al., 1990).
A second problem that must be considered is whether pMN cells give rise only
to motoneurons and oligodendrocytes or whether they also produce other cell
types. Various kinds of ventral spinal cord interneurons in zebrafish embryos
have been described by morphology but their origin is unknown
(Bernhardt et al., 1990
;
Bernhardt et al., 1992
;
Hale et al., 2001
). A complete
understanding of the mechanism by which Delta-Notch signaling regulates
motoneuron, oligodendrocyte and possibly interneuron specification will
require careful cell lineage analysis combined with conditional manipulation
of Notch signaling activity.
Delta-Notch signaling couples oligodendrocyte specification and
differentiation
Significantly, various data indicate that Notch signaling inhibits
oligodendrocyte differentiation. In vitro experiments showed that Notch
activity could inhibit differentiation of purified OPCs
(Wang et al., 1998), selective
inactivation of Notch1a in OPCs in vivo caused their premature differentiation
(Genoud et al., 2002
) and
oligodendrocytes became myelinated too soon in mice heterozygous for a
Notch1 mutation (Givogri et al.,
2002
). Additionally, astrocytes in demyelinating lesions of human
multiple sclerosis patients upregulated Jagged1, a Notch ligand, and Jagged1
blocked maturation of purified human OPCs
(John et al., 2002
). Our
observation that Notch1aac inhibited expression of
plp1/dm20 in vivo provides support for the idea that Notch signaling
regulates maturation of oligodendrocytes. Taken together with our
demonstration that Delta-Notch signaling promotes OPC formation, our work
indicates that Notch signaling both promotes specification of neural
precursors for oligodendrocyte fate and subsequently regulates their
differentiation (Fig. 7). Thus,
Notch activity couples the control of oligodendrocyte specification and
differentiation, which might help to match the development of myelinating
oligodendrocytes to their target axons.
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ACKNOWLEDGMENTS |
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