The Wolfson Institute for Biomedical Research and Department of Biology, University College London (UCL), Gower Street, London WC1E 6BT, UK
* Author for correspondence (e-mail: w.richardson{at}ucl.ac.uk)
Accepted 10 February 2005
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SUMMARY |
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Key words: Dbx, Cre, Spinal cord, Radial glia, Neurons, Astrocytes, Oligodendrocytes
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Introduction |
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Evidence for a restricted ventral source of OLPs seems to conflict with
other studies that favour more widespread generation of OLPs. For example,
immunohistochemical studies have suggested that radial glial cells can
transform into oligodendrocytes at the end of neuronogenesis; because radial
glia are present in all regions of the embryonic spinal cord VZ, this implies
that oligodendrocyte generation might also be widespread
(Choi et al., 1983;
Choi and Kim, 1985
;
Hirano and Goldman, 1988
).
Furthermore, studies based on transgenic mice that express lacZ under
transcriptional control of the myelin proteolipid protein (PLP/DM20)
gene suggest that there might be additional dorsal sources of OLPs, at least
in the cervical spinal cord and brainstem
(Spassky et al., 1998
). There
are also contradictory data from chick-quail chimeras that raise the
possibility of dorsal as well as ventral sources of OLPs in birds
(Cameron-Curry and Le-Douarin,
1995
; Pringle et al.,
1998
; Richardson et al.,
1997
).
In the present study, we used Cre-mediated recombination in transgenic mice
to follow the neuronal and glial fates of neural precursors in a restricted
part of the spinal cord neuroepithelium that expresses the transcription
factor Dbx1. The initial expression of Dbx1 (and Dbx2) spans four adjoining
domains of the neuroepithelium, two dorsal (dP5 and dP6) and two ventral (p0
and p1) (Pierani et al.,
2001). We demonstrate that, in addition to the expected
interneuron populations, both oligodendrocytes and astrocytes are generated
from the Dbx1/2 domain. The appearance of Dbx-derived cells with a hybrid
oligodendrocyte/radial glial antigenic phenotype and a radial morphology
suggests direct transformation of radial glia into oligodendrocytes, as was
suggested previously (Choi et al.,
1983
; Choi and Kim,
1985
; Hirano and Goldman,
1988
). The Dbx-derived oligodendrocytes comprise less than 5% of
the total oligodendrocyte population in the cord and have a more restricted
distribution, mainly settling in the lateral white matter radially opposite
their point of origin. In addition to oligodendrocytes, the Dbx1/2
neuroepithelium generates at least two classes of astrocytes fibrous
astrocytes in the white matter and protoplasmic astrocytes in the grey.
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Materials and methods |
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The modified PAC DNA was linearized by AscI digestion. PFGE was used to purify the PAC insert away from small vector fragments. This linear PAC DNA was concentrated into a 4% low-melting point agarose gel. Following ß-agarase (New England Biolabs) digestion and dialysis with microinjection buffer, the DNA was injected into pronuclei of fertilized mouse eggs. Transgenic mouse pups were screened for the presence of the Dbx1-iCre transgene by PCR and Southern blot (primer sequences available on request).
In situ hybridization and immunohistochemistry
Embryos were fixed in 4% (w/v) paraformaldehyde (PFA) in phosphate-buffered
saline (PBS). Generally, material was fixed overnight for in situ
hybridization, whereas fixation times for immunohistochemistry were varied
according to the age of the embryo and the epitope in question. Fixed embryos
were cryoprotected overnight in 20% (w/v) sucrose in PBS. Postnatal animals
were perfused with 4% (w/v) PFA through the right ventricle of the heart under
terminal anaesthesia. All tissues were embedded in Tissue-Tek OCT compound (R.
A. Lamb) and frozen on dry ice. Sections (5 to 15 µm) were cut on a
cryostat and collected on Superfrost Plus glass slides (BDH).
All solutions used for in situ hybridization were pre-treated with diethyl
pyrocarbonate (0.1% v/v). The following plasmids were used to generate
digoxigenin-labelled probes: mouse Dbx1, a 2 kb fragment spanning the
3' end of the coding sequence and the entire 3' UTR, from IMAGE
clone 426959 (UK HGMP Resource Centre); mouse Dbx2, a 500 bp PCR
product that includes parts of the final exon and the 3' UTR; mouse
Olig2, a 1.7 kb 3' BamHI-NcoI fragment
downstream of the open reading frame; mouse Nkx6.1, a 2.2 kb
full-length cDNA (gift from T. Jessell); and Mash1, a 700 bp fragment
that includes most of the coding sequence and part of the 3' UTR, from
IMAGE clone 481779 (UK HGMP Resource Centre). Details of the in situ
hybridization techniques have been described previously
(Pringle et al., 1996;
Fruttiger et al., 1999
)
(http://www.ucl.ac.uk/~ucbzwdr/MandM.htm)
For immunohistochemistry, the antibodies used were: rabbit anti-GFP, at
1:8000 dilution (AbCam); rabbit anti-Olig2 (a gift from D. Rowitch); mouse
monoclonal anti-RC2 IgM, at 1:5 dilution (Developmental Studies Hybridoma
Bank, DSHB); rat anti-PDGFR, at 1:500 (BD Biosciences); mouse
monoclonal anti-GFAP, at 1:400 (Sigma); guinea-pig anti-Sox10, at 1:2000 (a
gift from M. Wegner); monoclonal anti-NeuN, at 1:400 (Chemicon); monoclonal
anti-Pax7, at 1:10 (DSHB); monoclonal pan-Islet 4D5, at 1:20 (DSHB);
guinea-pig anti-Evx1, at 1:8000 (a gift from T. Jessell); monoclonal CC1, at
1:400 (Merck Biosciences); guinea pig anti-Lbx1, at 1:8000 (gift from T.
Jessell); monoclonal anti-Lim2, at 1:5 (DSHB); monoclonal anti-Lim3, at 1:20
(DSHB); and monoclonal anti-S100ß, at 1:400 (Sigma). Primary antibodies
were applied overnight at 4°C. Secondary antibodies were rhodamine-, AMCA-
or fluorescein-conjugated anti-rabbit, -goat, -rat, -guinea pig or -mouse IgM,
or anti-mouse IgG, at 1:200 (Pierce), and were applied for 60 minutes at room
temperature. To allow Olig2 and GFP double labelling, a goat anti-rabbit IgG
Fab fragment (Jackson) was used to effectively convert rabbit Olig2 into a
goat antibody, prior to detection with an anti-goat IgG secondary antibody.
All antibodies were diluted in PBS containing 10% serum and 0.1% (v/v) Triton
X-100. Following antibody treatment, sections were stained with Hoechst
(Sigma) and post-fixed for 5 minutes in 4% PFA. Sections were mounted under
coverslips in Citifluor anti-fade reagent (City University, UK).
Spinal cord cultures
Spinal cord cultures were prepared as previously described
(Kessaris et al., 2004).
Briefly, spinal cords from E12.5 mouse embryos were dissected away from
surrounding tissue in Hepes-buffered minimal essential medium (MEM-H)
(Invitrogen), and dissociated by incubation in 0.0125% (w/v) trypsin in
Earle's balanced salt solution (EBSS, Invitrogen) for 30 minutes at 37°C
in 5% CO2. The cells were mechanically dissociated in the presence
of DNaseI and seeded onto 13-mm poly-D-lysine-coated coverslips in a 50 µl
droplet of Dulbecco's modified Eagle's medium (DMEM, Invitrogen) containing
0.5% FCS at a density of 2.5x105 cells/coverslip. The cells
were allowed to attach for 30 minutes. Defined medium (350 µl)
(Bottenstein and Sato, 1979
)
was added and incubation continued at 37°C in 5% CO2.
Cyclopamine was used at a final concentration of 1 µM, and the FGFR
inhibitor PD173074 at 100 nM.
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Results |
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To establish the dorsal and ventral limits of Cre expression in the
neuroepithelium, we crossed the Dbx1-Cre mice to the
Rosa26-GFP reporter line (Mao et
al., 2001) and analyzed the offspring at embryonic day 10.5
(E10.5) by in situ hybridization. GFP expression was activated in a broad
neuroepithelial domain, wider than the domain of Dbx1 expression at
the same age and corresponding more closely to that of Dbx2
expression (Fig. 2A-C). This is
consistent with previous reports that Dbx1 is initially expressed
(prior to E10.5) in an identical pattern to Dbx2 and only narrows
down later (Pierani et al.,
2001
). The region of GFP activation therefore probably corresponds
to the early Dbx1/Dbx2 co-expression domain. The ventral limit of GFP
expression abuts the dorsal limit of Nkx6.1 expression, many cell
diameters away from the Olig2-expressing domain in pMN
(Fig. 2D-F). This is consistent
with previous data showing mutually exclusive expression of Nkx6.1
and Dbx2 in the spinal cord
(Briscoe et al., 2000
). The
dorsal limit of GFP activation overlaps with Mash1 and Pax7, which
are expressed within dP5 or dP6, respectively, at their ventral limit
(Fig. 2G-I)
(Caspary and Anderson, 2003
;
Helms and Johnson, 2003
).
Collectively, the data demonstrate that expression of iCre is restricted to
Dbx1/Dbx2-positive neuroepithelial precursors, and activation of the
GFP reporter gene is therefore restricted to four domains of the
neuroepithelium: dP5, dP6, P0 and P1 (Fig.
1E).
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Radial glia are generated from the Dbx neuroepithelium
Radial glia were one of the first cell types to express GFP in
Dbx1-CrexRosa26-GFP offspring
(Fig. 4A-F). They had a typical
radial glial morphology with a single thin process extending from the
ventricular zone all the way to the pial surface (reviewed by
Bentivoglio and Mazzarello,
1999). Immunolabelling with monoclonal antibody RC2 showed
co-localization along the entire length of the process
(Fig. 4A-F). Co-expression of
RC2 and GFP persisted throughout embryogenesis. However, the morphology of
these cells changed with time. From E15.5, an increasing number of (RC2, GFP)
double-labelled cells appeared to translocate their cell bodies close to the
pial surface (shown in Fig.
4G-L at E16.5) and to change their antigenic profile (see below).
We thought it possible that these might correspond to radial glial cells in
the process of transforming into astrocytes and/or oligodendrocytes at the end
of neuronogenesis (Schmechel and Rakic,
1979
; Choi et al.,
1983
; Choi and Kim,
1985
; Hirano and Goldman,
1988
; Voigt,
1989
).
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Oligodendrocyte generation from Dbx-expressing precursors is independent of Shh signalling
The Dbx-expressing neuroepithelium is exposed to low levels of Shh in vivo
and neuronal specification within the Dbx domain depends on signals other than
Shh (Pierani et al., 1999).
The emergence of oligodendrocytes from this region was therefore surprising
given the known requirement for Shh in specifying OLPs in the ventral pMN
domain. FGF has recently been shown to be capable of promoting oligodendrocyte
specification in cultures of neural precursors from embryonic cerebral cortex
or spinal cord (Chandran et al.,
2003
; Kessaris et al.,
2004
). To determine the signalling requirements for the generation
of Dbx-derived oligodendrocytes in vitro, we dissociated embryonic spinal
cords from Dbx1-iCrexRosa26-GFP mice at E12.5,
approximately three days before the first appearance of Dbx-derived
oligodendrocyte lineage cells in vivo, and cultured the cells in the presence
of the hedghog inhibitor cyclopamine
(Cooper et al., 1998
;
Incardona et al., 1998
) or the
Fgfr inhibitor PD173074 (Skaper et al.,
2000
). In the absence of any inhibitors, GFP-labelled
oligodendrocytes identified by co-labelling with anti-Sox10 antibody
developed in vitro within 5 days
(Fig. 7A,E). Their development
was not inhibited by cyclopamine (Fig.
7B,E) but was completely abolished by PD173074
(Fig. 7C-E), indicating a
strict requirement for FGF signalling.
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Discussion |
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A source(s) of oligodendrocytes outside pMN
Our experiments show unequivocally that some oligodendrocytes are generated
from the Dbx neuroepithelial domain. We estimate that the Dbx-derived
population comprises around 3% of all Sox10-positive oligodendrocyte lineage
cells. This might be an underestimate, for not all of the neuroepithelial
cells in the Dbx domain were GFP-labelled in all sections, presumably because
of the transient nature of Dbx1-iCre expression. However, a majority of
Dbx-expressing neuroepithelial cells was always labelled, so we think it
unlikely that their real contribution to oligodendrocyte production is more
than 5%. Most of the remainder presumably come from pMN, although further
sub-populations of oligodendrocytes might turn out to be derived from outside
either pMN or the Dbx domain (for a summary, see
Fig. 9). It would be
interesting to determine whether the Dbx-derived oligodendrocytes are
functionally different from the rest. They are found predominantly in the
lateral white matter suggesting that their progenitors might migrate less
widely than the majority do.
|
The dorsally derived oligodendrocyte lineage cells expressed the same markers as their ventrally derived counterparts at least those we tested (Olig2, Sox10, Pdgfra and CC1). Thus, we have found no evidence so far that the dorsally derived subpopulation is antigenically distinct.
Shh-independent oligodendrogenesis in the dorsal spinal cord
Shh released from the floor plate and notochord is essential for the
development of OLPs in the ventral spinal cord. Chandran et al. recently
showed that neural stem cells derived from dorsal spinal cord can be induced
by FGF2 to generate OLPs in vitro
(Chandran et al., 2003). The
same was shown for embryonic cortical precursors by Kessaris et al.
(Kessaris et al., 2004
). In
this study, we made use of Dbx1-CrexRosa26-GFP mice to
identify neural precursors derived specifically from the Dbx domain in
embryonic spinal cord cultures. Our experiments showed that OLPs can develop
from Dbx-derived precursors independently of Shh (i.e. development is not
inhibited by cyclopamine), consistent with a previous report of
Shh-independent specification of interneurons in this region
(Pierani et al., 1999
). We
also showed that OLP development from Dbx-positive spinal cord precursors
requires FGF signalling in vitro. To discover whether FGF signalling is
actually implicated in vivo would require specific inhibition of FGF
signalling in the dorsal spinal cord; this is difficult to contemplate at
present because we do not know which of the large number of FGF family members
is involved or indeed which FGF receptor.
The relationship between radial glia and oligodendrocytes
Some of the first cells to be labelled with GFP in our reporter mice were
radial glia. The nuclei of these cells are initially located in or close to
the VZ, and their radial processes extend to the pial surface. By analogy with
radial glia in the brain, it seems likely that they correspond to the
neuroepithelial precursors themselves
(Malatesta et al., 2003;
Anthony et al., 2004
). From
E15.5, when the radial glial cell bodies moved towards the pial surface, we
observed co-expression of RC2 and the oligodendrocyte lineage markers Olig2 or
Sox10 in some radially oriented cells, suggesting that the radial glia
transform directly into oligodendrocytes. This supports previous evidence that
spinal cord radial glia can give rise to oligodendrocytes as well as
astrocytes after neuron generation has ceased
(Choi et al., 1983
;
Choi and Kim, 1985
;
Hirano and Goldman, 1988
).
It is not clear whether the mode of OLP generation from Dbx-expressing precursors is fundamentally different from their mode of generation in the ventral cord. pMN-derived OLPs are presumably derived from radial glia too, as the latter are now thought to correspond to stem cells that generate all the neurons and glia of the CNS. However, the pMN-derived OLPs arise close to the ventricular surface, whereas we first detected Dbx-derived OLPs towards the pial surface. This presumably relates to the position of the radial glial cell bodies at the time they start to express oligodendrocyte lineage markers such as Pdgfra, Sox10 or Olig2. Another difference seems to lie in how widely the OLPs disseminate after they are formed; those formed early from pMN proliferate rapidly at first and migrate away from pMN in all directions, whereas the later-forming Dbx-derived OLPs proliferate less strongly, if at all, and migrate less widely. It remains to be determined whether these different behaviours reflect different inducing signals (Shh versus FGF, say), different environments in the cord at early versus late embryonic stages, or some intrinsic difference between the ventral and dorsal subsets.
Two types of astrocytes are generated from the Dbx domain
In addition to interneurons and oligodendrocytes, at least two
morphological subtypes of astrocytes were generated from the Dbx domain.
Protoplasmic astrocytes had a typical spherical outline with an extensive and
intricate network of sheet-like branching processes and were distributed
widely within the grey matter of the spinal cord. They were frequently
associated with the cell bodies of neurons in both the dorsal and ventral
cord, including motoneurons. Fibrous astrocytes, however, had a restricted
distribution within the lateral white matter, in those regions previously
occupied by the distal ends of the radial glia processes. The latter
observation is consistent with the idea that some radial glia transform
directly into fibrous astrocytes at the end of neuronogenesis
(Schmechel and Rakic, 1979;
Voigt, 1989
) (for a review,
see Goldman, 2001
).
Our Dbx1-iCre mice label the progeny of four neuroepithelial domains p1, p0, dP6 and dP5 so we cannot tell whether each one of these domains generates all of the glial cell types described here or whether different subsets of glia are generated from each individual domain, as has been shown for neurons. Resolution of this question would require targeting of the Cre transgene to individual neuroepithelial domains within the broader Dbx domain; however, this is not possible with currently available Cre deleter strains.
Dbx-neuroepithelial cells do not generate ependymal cells
We observed that Dbx1/Dbx2 precursors do not contribute to the
ependymal layer that surrounds the reduced lumen of the postnatal and adult
spinal cord, adding to previous evidence that ependymal cells are derived
entirely from ventral (Nkx6.1-expressing) neuroepithelium
(Richardson et al., 1997;
Fu et al., 2003
).
Nevertheless, a subset of the Dbx-derived protoplasmic astrocytes settles
close to the postnatal ependymal layer where they form narrow bilateral
columns of cells along the length of the spinal cord. It is interesting to
speculate that these might correspond to a subset of `subependymal astrocytes'
analogous to those that have been described as neural stem cells in the
postnatal telencephalon (Doetsch et al.,
1999
).
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Note added in proof |
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ACKNOWLEDGMENTS |
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