Departments of Pathology and Developmental and Cell Biology, University of California, Irvine, D440 Medical Sciences I, Irvine, CA 92697-4800, USA
* Author for correspondence (e-mail: emonuki{at}uci.edu)
Accepted 23 May 2005
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SUMMARY |
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Key words: Roof plate, Fate map, Genetic ablation, Bmp, Gdf7, Transgenic mice, Cre recombinase, Diphtheria toxin, Mouse
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Introduction |
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CP forms in three locations at or near the dorsal midline of the central
nervous system (CNS) in the hindbrain roof (myelencephalic CP of the
4th ventricle), in the anterior diencephalic roof (diencephalic CP of the 3rd
ventricle), and at the dorsomedial edges of the telencephalon bilaterally
(telencephalic CP of the lateral ventricles)
(Fig. 1A). CP contains both
epithelial and mesenchymal (stromal) components, with the CP epithelium (CPe)
facing the ventricular lumen. CPe is a single-layered cuboidal to columnar
epithelium that is contiguous with adjacent pseudostratified neuroepithelium.
At all sites of CPe formation in mice, differentiation into a simple
epithelium occurs by embryonic day 12.5 (E12.5)
(Sturrock, 1979) and is
accompanied by activation of the CPe-specific gene transthyretin
(Ttr) (Harms et al.,
1991
; Herbert et al.,
1986
). Interactions between the epithelium and mesenchyme
(Wilting and Christ, 1989
) are
then thought to transform the CP into a true vascular plexus with its hallmark
papillary architecture.
The embryonic dorsal midline (DM) is a well known CNS patterning center
(Chizhikov and Millen, 2005;
Furuta et al., 1997
;
Lee et al., 2000a
;
Liem et al., 1997
;
Millonig et al., 2000
;
Monuki et al., 2001
) that is
ideally positioned to regulate CP development
(Fig. 1A). The DM includes the
roof plate (RP), the midline `roof' of the neural tube that forms when the
neural plate fuses. In mice, neural plate fusion begins in the
occipital/cervical region at E8.0-8.5, then proceeds rostrally and caudally,
with fusion in the forebrain occurring during the E8.5-9.0 period
(Kaufman and Bard, 1999
). The
RP specifies and patterns dorsal neural tissues via signaling proteins, most
notably the bone morphogenetic proteins (Bmps)
(Furuta et al., 1997
;
Lee et al., 2000a
;
Liem et al., 1997
). In the
telencephalon, the RP is closely associated with the telencephalic CPe (tCPe)
and cortical hem (Fig. 1B),
where both Bmps and Wnts are expressed
(Grove et al., 1998
;
Lee et al., 2000b
). Owing to
imprecision in defining the spatiotemporal boundaries between the RP, tCPe and
hem, we refer to this region collectively as the `DM' at neural tube stages
(E9.5-10.5). At later stages, when hem and tCPe differentiation are apparent
(e.g. E11.5-12.5), we refer to this region as the `dorsomedial telencephalon'
(DMT) (Fig. 1B).
Despite the likelihood of important DM-CP relationships, remarkably little
evidence for such relationships exist. Genetic fate mapping has suggested
lineage relationships between DM and CPe cells in the hindbrain
(Awatramani et al., 2003). In
the telencephalon, inactivations of the BmpRIa receptor indicated a
requirement for local high-level Bmp signaling in tCPe induction
(Hebert et al., 2002
). We have
previously reported studies with two Gdf7 transgenic mouse lines
Gdf7Cre and Gdf7DTA (Lee et al.,
2000a
) that allowed for selective fate mapping or ablation
of Gdf7-expressing DM cells (Monuki et
al., 2001
). Gdf7-mediated ablations resulted in CPe loss, but the
CPe phenotype was confounded by an open neural tube defect that involved the
forebrain (Monuki et al.,
2001
). In this study, we used two Gdf7-mediated ablation
strategies that correct the open forebrain defect, together with detailed
genetic fate mapping and apoptosis studies, to demonstrate intimate DM-CPe
relationships at all sites of CP formation.
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Materials and methods |
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X-gal histochemistry, in situ hybridization, histology and TUNEL assays
These were performed as described
(Monuki et al., 2001) with the
following modifications: (1) for X-gal staining, embryos were fixed at 4°C
in either 4% paraformaldehyde (1-2 hours) or 0.2-0.4% paraformaldehyde (4
hours to overnight) supplemented with 2 mM MgCl2 and 5 mM EGTA; (2)
for section in situ hybridization, Proteinase K digestion was omitted, and
coverslips were elevated using PCR sealing tape to reduce edge artifact and
minimize tissue disruption. Paraffin sections were processed and sectioned by
the UCI Pathology Services Core. The following in situ hybridization probe
templates were used: mouse Ttr EST (IMAGE clone 1078224, Accession Number
AA822938), mouse Gdf7 cDNA (from Candice Crocker and Anne Calof), mouse Bmp4,
Bmp6 and Bmp7 cDNAs (from Julie Lauterborn)
(Furuta et al., 1997
), and
mouse Msx1 EST (IMAGE clone 903377, Accession Number AA518368). Fluorescent
TUNEL was performed according to manufacturer protocol (Apoptag kit,
Serologicals) with Hoechst 33342 (Molecular Probes) nuclear counterstaining on
10-20 µm cryosections. Images were captured by Spot RT digital imaging on a
Nikon SMZ1500 stereodissecting microscope or upright Nikon E600 microscope
with bright-field, DIC or fluorescence optics. For comparative studies (mutant
versus littermate controls, serial section analysis), processing steps and
assays were carried out in parallel, and images were captured using identical
camera settings and image enhancements. In the few cases where littermate
control sections were unavailable, wild-type sections were used.
qRT-PCR
Real-time semi-quantitative RT-PCR was established using rigorous quality
controls (Stankovic and Corfas,
2003) to validate all assumptions embedded in the standard
Ct method for quantifying relative expression levels
(Livak and Schmittgen, 2001
).
Mouse 18S (Stankovic and Corfas,
2003
), cyclophilin A and intron-spanning Ttr primers from
PrimerBank (Wang and Seed,
2003
) were commercially prepared (Qiagen) and verified for
amplification efficiency and constancy over four to six logs of template
concentration on an Opticon System (MJ Research) using SYBR-Green-containing
master mixes (MJ Research/Biorad). Amplicon sizes were verified by gel
electrophoresis; the Ttr amplicon was also confirmed by sequencing. Among four
internal references tested (18S, CYPA, GAPDH, actin), 18S and CYPA varied the
least between E12.5 ACTBCre;Gdf7DTA mutants and littermate controls. Total
dorsal forebrain RNA was column purified (Aurum mini kit, Biorad), then
reverse transcribed with MMLV RT (Promega) and random primers. 18S QPCR was
performed on all corresponding cDNA and RNA samples; all
CtcDNA-RNA are at least 16.7 (mean 20.9), which
indicates a cDNA:genomic target ratio of more than 105. Ttr
measurements in three E12.5 ACTBCre;Gdf7DTA mutant and three control
littermate samples were performed in duplicate in a single experimental run.
One obvious outlier Ct value was discarded; all other samples were well
duplicated (
Ct<0.5). Duplicate Ct, normalized
Ct
(CtTtr Ctreference),
Ct (
Ctmutant average
Ctcontrol), and relative
level (2
Ct) means and s.e.m. were calculated
in Excel and graphed in KaleidaGraph.
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Results |
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By E10.5, X-gal staining became stronger and remained confined to the DM (Fig. 2C-G). In the telencephalon, the labeled DM domain was broader than that in the diencephalon, and these two domains were separated by weaker staining at the midline between the telencephalon and diencephalon (the di-telencephalic midline boundary; Fig. 2C). Sections through the telencephalon demonstrated primary localization of labeled cells to DM neuroepithelium, including the RP. Many, but not all telencephalic DM cells were labeled, and the intracellular labeling patterns were suggestive of recent lacZ expression onset (i.e. X-gal staining in perinuclear organelles rather than diffusely in the cytoplasm; Fig. 2E,G).
Few, if any, labeled cells were found away from the telencephalic DM anteriorly, laterally in the cortical primordia, or radially in overlying mesenchyme and epidermal ectoderm. Confinement to the DM was also relatively strict in the hindbrain, diencephalon and midbrain at E10.5 (Fig. 2C,D,F). The location of Gdf7 transcripts in wild-type E10.5 embryos, as detected by in situ hybridization, matched the genetic fate map well (Fig. 2H, see Fig. 10B). Thus, at neural tube stages (E9.5-10.5), Gdf7 activation is restricted to DM neuroepithelial cells throughout the developing CNS.
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In contrast to the anterior DMT, posterior levels of the DMT where the majority of tCPe cells reside were devoid of Gdf7 cell lineages (Fig. 4B,C,E,F,K,L). The rostrocaudal level at which labeled tCPe and hem cells were no longer detectable approximated the level of the di-telencephalic midline boundary (Fig. 4). This suggested that anterior tCPe and hem cells are lineally related to Gdf7-expressing DM cells of neural tube stage embryos, while posterior tCPe and hem cells are not. The lack of posterior labeling was not due to mosaicism or inefficiency in R26R lacZ expression, as ACTBCre;R26R embryos demonstrated robust lacZ expression in apparently all tCPe and hem cells (data not shown). Likewise, Gdf7Cre mosaicism or insensitivity appears unlikely to account for the fate-mapping results, based on studies in ACTBCre;Gdf7DTA embryos (see below).
`Late' Gdf7-mediated ablation causes reduced mCPe and dCPe, but preserved tCPe
To confirm the genetic fate map, we mated Gdf7Cre to conditional Gdf7DTA
(diphtheria toxin A chain) mice (Lee et
al., 2000a; Monuki et al.,
2001
). In addition to optimal fidelity for Gdf7 cell lineages
both Cre and DTA should be restricted to Gdf7-expressing cells, thus
minimizing transgene `leakiness' Gdf7Cre-mediated ablation should be
delayed (`late') compared with ablations using ACTBCre mice. In
ACTBCre;Gdf7DTA embryos, Gdf7DTA allele recombination should occur
during very early embryogenesis (ACTBCre is expressed as early as the
four-cell stage) (Lewandoski et al.,
1997
), resulting in ablation that coincides with the onset of Gdf7
expression. The same allele in Gdf7Cre;Gdf7DTA animals should not recombine
until some time after Gdf7 expression onset, causing ablation to be relatively
delayed. In contrast to the ACTBCre;Gdf7DTA phenotype (see below),
Gdf7Cre;Gdf7DTA embryos were externally normal and viable through at least
E16.5.
As predicted from the hindbrain and diencephalon fate maps
(Fig. 3), late ablation
resulted in reduced mCPe and dCPe. In E14.5 Gdf7Cre;Gdf7DTA embryos, mCPe
reduction was grossly visible through the translucent hindbrain roof (data not
shown). Ttr expression in the hindbrain and diencephalon was reduced at E12.5
(Fig. 5A,I) and E14.5
(Fig. 5C,K). Interestingly, Ttr
expression remained detectable in both regions, particularly in the hindbrain.
This raised the possibility that DTA-mediated ablation might still be ongoing
at E14.5. As DTA causes cell death by inducing apoptosis
(Komatsu et al., 1998), we
used TUNEL assays to identify potential sites of ongoing DTA delivery.
Significant apoptosis was present selectively in the residual dCPe and mCPe of
E14.5 mutants (Fig. 5E,M), but
not in control littermates or in other nearby tissues. By E16.5, papillary CP
tissue was markedly reduced in both the hindbrain and diencephalon
(Fig. 5G,O).
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To study the tCPe and dCPe fields in developing mice with a molecular
marker, we examined Ttr expression in serial coronal sections. At E11.5, Ttr
expression was detectable in the emerging tCPe bilaterally, but not yet in the
diencephalon (Fig. 7A,B). Ttr
expression became evident in dCPe by E12.5
(Fig. 7E,F), consistent with
the conserved order of CP development in many species (i.e. tCP prior to dCP)
(Dohrmann, 1970;
Dziegielewska et al., 2001
). In
multiple embryos examined, Ttr expression was invariably separated into
midline diencephalic and bilateral telencephalic fields by the Ttr-negative
choroid plaque (Fig. 7A,D,E) and anterior diencephalic neuroepithelium
(Fig. 7E,F). This indicated
that the three forebrain CPe fields (two tCPe and one dCPe) are initially
separate.
Apoptosis in `early' Gdf7-mediated ablations coincides with the Gdf7 fate map
In order to ablate Gdf7-expressing cells at neural tube stages, we
generated ACTBCre;Gdf7DTA embryos. In addition to synchronizing the ablation
to Gdf7 expression onset, ACTBCre;Gdf7DTA embryos should be highly sensitive
indicators of Gdf7 expression. Strong ACTBCre expression early in development
(Lewandoski et al., 1997)
results in little to no Cre mosaicism using this line
(Meyers et al., 1998
), which
was confirmed in ACTBCre;R26R embryos (data not shown). In addition, as little
as one DTA molecule can kill a cell
(Yamaizumi et al., 1978
),
which makes cell death a sensitive readout of Gdf7 expression in
ACTBCre;Gdf7DTA embryos.
As matings with ACTBCre mice on a mostly C57BL/6 background yielded
confounding open forebrain defects (Monuki
et al., 2001), we changed strain background in an attempt to
correct the open forebrain phenotype. ACTBCre mice
(Lewandoski et al., 1997
) on
an FVB/N background (Jackson Labs), when mated to the Gdf7DTA line, yielded
ACTBCre;Gdf7DTA embryos with closed forebrains in nearly 100% of cases (96/98
double transgenic embryos). Viable mutant embryos could be obtained through at
least E14.5. More caudal CNS regions (including the hindbrain) remained open,
as seen previously (Monuki et al.,
2001
), but the telencephalon and anterior diencephalon
where tCPe and dCPe form were almost invariably closed.
|
At E10.5 and E11.5, apoptosis levels in the mutant telencephalon were low, but appreciable at the anterior midline (Fig. 8G,M), while significant TUNEL staining was absent at more posterior levels (Fig. 8H-I,N-O). This pattern was well matched to the apoptosis patterns seen in control littermates (Fig. 8J-L,P-R) and to the Gdf7 fate map (Fig. 4). These correspondences, together with the sensitivity of ACTBCre;Gdf7DTA embryos, confirm that the posterior tCPe domain lacks a significant cohort of Gdf7-expressing DM cell lineages. They also indicate that DM cell ablation at neural tube stages is the primary insult responsible for subsequent ACTBCre;Gdf7DTA phenotypes; we therefore refer to the ACTBCre;Gdf7DTA studies as `DM cell ablations.'
Apoptosis in control embryos distinguishes the anterior and posterior tCPe domains
The anterior and posterior tCPe domains distinguished by Gdf7 fate mapping
showed different patterns of apoptosis in normal embryos. At both E10.5 and
E11.5, significant apoptosis was detectable in the choroid plaque and anterior
tCPe (Fig. 8J,P), but not in
the posterior tCPe domain (Fig.
8K-L,Q-R). As in the fate-mapping studies, the boundary between
anterior and posterior tCPe domains detected by TUNEL was located lateral to,
and at roughly the same rostrocaudal level as, the di-telencephalic midline
boundary (Fig. 8).
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To determine whether the reduced Bmp levels led to reduced Bmp signaling,
we examined Msx1 expression, a standard marker of high-level Bmp signaling in
the developing forebrain (Furuta et al.,
1997; Hebert et al.,
2002
; Shimamura and
Rubenstein, 1997
). In normal embryos, Msx1 expression correlated
well with sites of high-level Bmp expression, including the bilateral tCPe
anlagen at E10.5 (Fig. 10L)
and the definitive tCPe at E12.5 (Fig.
10N). In E10.5 and E12.5 ACTBCre;Gdf7DTA embryos, neuroepithelial
Msx1 expression was almost completely absent, while expression persisted in
the attenuated non-neural tissues overlying the neuroepithelium
(Fig. 10G,I,K,M). Thus,
high-level neuroepithelial Bmp signaling was almost completely abrogated after
DM cell ablation.
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Discussion |
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DM-CPe relationships in the hindbrain and diencephalon
Classical morphological studies have long suggested that the RP invaginates
and directly becomes mCPe and dCPe
(Dohrmann, 1970). A more recent
study, which employed intersectional fate mapping with Wnt1 and Hoxa2-driven
Cre and Flp lines, also concluded that the hindbrain RP and mCPe are derived
from the same embryonic primordium
(Awatramani et al., 2003
). Our
studies are consistent with these conclusions; however, it should be noted
again that our fate-mapping data in the hindbrain and diencephalon are not
conclusive with regard to lineage. As discussed earlier, Gdf7-expressing mCPe
and dCPe cells could be derived from Gdf7-negative precursors, although it
seems highly unlikely that such lineages account for all of the mCPe and
dCPe.
DM cell lineages in the telencephalon
In the telencephalon, the lack of Gdf7 transcripts after E10.5
(Fig. 4G-I) makes lineage
assignment based on the genetic fate map more definitive. Based on this map,
Gdf7 cell lineages at E11.5-12.5 are primarily found in the choroid plaque,
tCPe and cortical hem of the anterior DMT. We have previously shown that Gdf7
lineages also include cortical marginal zone (MZ) neurons that appear to
originate from the cortical hem (Monuki et
al., 2001). The hem is a significant source of MZ neurons
(Meyer et al., 2002
;
Takiguchi-Hayashi et al.,
2004
), but our current study indicates that only a small fraction
of hem cells and their MZ progeny belong to Gdf7 lineages.
Three different genetic strategies (Gdf7Cre;R26R, Gdf7Cre;Gdf7DTA, ACTBCre;Gdf7DTA) provided evidence that Gdf7 cell lineages do not contribute significantly to the posterior DMT. Cre mosaicism or insensitivity seems insufficient to account for these findings for at least two reasons. First, Gdf7 fate mapping with Gdf7Cre;R26R embryos was more sensitive than Gdf7 in situ hybridization in the telencephalon (compare Fig. 2, Fig. 4 and Fig. 10B). Second, as discussed earlier, the ACTBCre;Gdf7DTA studies were highly unlikely to suffer from significant mosaicism or insensitivity. Indeed, ACTBCre;Gdf7DTA embryos should be among the least mosaic and most sensitive Gdf7 expression indicators possible using mouse genetics. Thus, the absence of significant apoptosis away from the anterior midline of ACTBCre;Gdf7DTA embryos (Fig. 8) makes it highly unlikely that Gdf7 cell lineages constitute a significant fraction of the posterior DMT.
The anterior and posterior domains of tCPe
The tCPe domains distinguished by Gdf7 fate mapping
(Fig. 4) and apoptosis
(Fig. 8) are separated by a
boundary that is not apparent morphologically
(Fig. 11B). This `cryptic'
tCPe boundary appears to be analogous to those described recently in the
hindbrain DM and CPe (Awatramani et al.,
2003); such cryptic boundaries may therefore be general features
of the DM and CPe. The Gdf7 cell lineages themselves may undergo apoptosis in
the anterior tCPe. These lineages constitute a decreasing fraction of anterior
tCPe and other DMT cells over time (Fig.
4; data not shown), suggesting higher apoptosis:proliferation
ratios in Gdf7 cell lineages compared with their neighbors. These lineages
also cluster towards the base of tCPe at later stages (e.g.
Fig. 4J), where apoptosis may
be selectively seen (Fig.
6G,H).
Interestingly, anterior and posterior domains within human tCPe, with
features remarkably similar to those described in our study, have been
described in a classic monograph (Bailey,
1915). In this neuroanatomical study of human embryos, Bailey
concluded that the anterior tCPe is derived directly from the paraphyseal
arch, the region of telencephalic RP just anterior to the transverse fold
(velum transversum) that demarcates the boundary between telencephalic and
diencephalic RP. Anterior tCPe is continuous with and lateral to the
paraphyseal arch, where it forms in the `area choroidea anterior.' Temporally,
anterior tCPe differentiation occurs slightly ahead of the posterior tCPe,
which is much more voluminous and forms in the `area choroidea posterior'
along the medial telencephalic wall. Our study fully supports these
conclusions, including the direct derivation of anterior tCPe cells from the
RP (DM), the separate derivation of posterior tCPe from the medial
telencephalic wall, and the anteroposterior tCPe boundary being located
lateral to, and at a similar rostrocaudal level as, the velum transversum
(di-telencephalic midline boundary). The similarities between our mouse
studies and the Bailey monograph on human embryos suggest a common tCPe
substructure that is likely to be shared among mammals.
The non-cell-autonomous DM-tCPe relationship
Our studies suggest a model in which DM cells act non-cell-autonomously to
generate high-level Bmp signaling in the posterior tCPe anlagen, which
subsequently leads to CPe induction
(Hebert et al., 2002)
(Fig. 11C). Lower-level Bmp
signaling, as seen in the normal choroid plaque (Figs
7,
10) and in the midline after
DM cell ablation (Figs 9,
10), is insufficient to induce
CPe. As DM cells have no apparent influence on cell survival in the posterior
tCPe domain (Fig. 8), the DM
cells are likely to generate high-level Bmp signaling via an active inductive
process. The critical period for this non-cell-autonomous process includes
E9.0-9.5, based on the timing of DM cell ablation in ACTBCre;Gdf7DTA embryos
(Fig. 8); ablation in
Gdf7Cre;Gdf7DTA embryos occurs after the inductive period
(Fig. 6). E9.0-9.5 would
overlap the permissive period for inducing CPe in mouse forebrain cells
(E8.5-9.5) (Thomas and Dziadek,
1993
).
The likelihood that DM cells not only become tCPe cells, but also induce
them non-cell-autonomously, implies that homeogenetic mechanisms are involved
in tCPe induction. Homeogenetic induction i.e. the ability of a cell
to induce its neighbor to adopt a fate similar to its own is a well
known feature of the ventral (Placzek et
al., 1993) and dorsal (Liem et
al., 1995
) midlines in the developing spinal region, and has been
described for Gdf7-expressing RP cells near the isthmus organizer
(Alexandre and Wassef, 2003
).
In addition to inducing posterior tCPe cells, homeogenetic mechanisms may be
involved in the anterior domain, where tCPe cells derived from Gdf7-negative
precursors also fail to form after Gdf7-mediated ablation. Bmps mediate
homeogenesis in the dorsal spinal cord
(Liem et al., 1997
;
Liem et al., 1995
) and may be
the crucial homeogenetic signals in tCPe induction
(Fig. 10, Fig. 11C). Indeed, the
residual midline domains of Bmp4 and Bmp6 following DM cell ablation
(Fig. 10C,E) would be
consistent with a failure of Bmp production to spread homeogenetically from
the DM into the tCPe anlagen.
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ACKNOWLEDGMENTS |
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