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First published online 3 October 2007
doi: 10.1242/dev.004325
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Research Report |
1 Departments of Neuroscience and Molecular Genetics, Albert Einstein College of
Medicine, Bronx, NY 10461, USA.
2 Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021,
USA.
3 Department of Biological Sciences, Stanford University, Stanford, CA,
USA.
* Author for correspondence (e-mail: jhebert{at}aecom.yu.edu)
Accepted 29 August 2007
SUMMARY
Holoprosencephaly (HPE) is a devastating forebrain abnormality with a range of morphological defects characterized by loss of midline tissue. In the telencephalon, the embryonic precursor of the cerebral hemispheres, specialized cell types form a midline that separates the hemispheres. In the present study, deletion of the BMP receptor genes, Bmpr1b and Bmpr1a, in the mouse telencephalon results in a loss of all dorsal midline cell types without affecting the specification of cortical and ventral precursors. In the holoprosencephalic Shh-/- mutant, by contrast, ventral patterning is disrupted, whereas the dorsal midline initially forms. This suggests that two separate developmental mechanisms can underlie the ontogeny of HPE. The Bmpr1a;Bmpr1b mutant provides a model for a subclass of HPE in humans: midline inter-hemispheric HPE.
Key words: Telencephalon, Dorsal midline, Choroid plexus, Cortical hem, Holoprosencephaly, BMP, SHH
INTRODUCTION
The cerebral hemispheres, the seat of higher cognitive function in mammals, develop from the embryonic telencephalon. The telencephalon becomes divided into morphologically distinct left and right hemispheres shortly after neural tube closure. Dorsally, the hemispheres are separated by two midline cell types: the choroid plexus, which produces the cerebrospinal fluid, and the cortical hem, which lies between the choroid plexus and hippocampal primordium. The molecular pathways that generate these midline cell types are poorly understood.
Holoprosencephaly (HPE), the most common congenital forebrain defect in
humans (Wallis and Muenke,
2000
; Muenke and Beachy,
2000), is characterized by a loss of midline tissue. The large
spectrum of phenotypic severity and midline areas affected in inherited cases
of human HPE are consistent with a complexity of genetic pathways regulating
midline formation (Nanni et al.,
1999; Ming and Muenke,
2002). In only a minority of HPE cases have mutations at known
genetic loci been identified (Wallis and
Muenke, 2000; Muenke and
Beachy, 2000). In most identified cases, the mutated genes
normally function in the ventral telencephalon. Disruption of the ventrally
acting SHH or Nodal signaling pathways leads to HPE
(Wallis and Muenke, 2000;
Muenke and Beachy, 2000;
Hayhurst and McConnell, 2003)
and although not yet linked to HPE in humans, loss-of-function mutations in
the mouse genes Cdo (Cdon - Mouse Genome Informatics; which
encodes a multifunctional transmembrane protein), Lrp2 (a low-density
lipoprotein-related receptor) and Chrd and Nog (secreted BMP
antagonists), exhibit loss of SHH expression and HPE
(Anderson et al., 2002;
Zhang et al., 2006;
Spoelgen et al., 2005).
Of the genes known to cause HPE in mice, only mutations in Lrp2,
Chrd;Nog, Zic2 and Fgf8 have been reported to display
clear alterations in dorsal midline development
(Anderson et al., 2002;
Spoelgen et al., 2005;
Nagai et al., 2000;
Storm et al., 2006). Whereas
Lrp2 and Chrd;Nog mutants exhibit excessive dorsal
midline features such as BMP expression and apoptosis
(Furuta et al., 1997;
Anderson et al., 2002;
Spoelgen et al., 2005), the
dorsal midline appears to be lost in the holoprosencephalic Zic2 and
Fgf8 hypomorphic mutants (Nagai
et al., 2000; Storm et al.,
2006). ZIC2 is also the only locus implicated in a
subclass of HPE in humans, the midline inter-hemispheric HPE (MIH), which is
associated with impaired dorsal midline formation, whereas in other classes of
HPE the ventral medial area is primarily affected
(Barkovich and Quint, 1993;
Simon et al., 2002;
Marcorelles et al., 2002;
Nagai et al., 2000). Note that
most ZIC2 mutations also affect ventral midline formation
(Brown et al., 2001).
Bmp2, 4, 5, 6 and 7 are expressed in the dorsal midline,
prior to separation of the hemispheres
(Furuta et al., 1997). The
receptors are expressed broadly in telencephalic precursor cells. BMP4-soaked
beads placed on explants of lateral telencephalon induce midline features
(apoptosis and Msx1 expression) and inhibit lateral features
[proliferation and Foxg1 expression
(Furuta et al., 1997)]. BMP
signaling is also crucial in specifying choroid plexus development
(Panchision et al., 2001;
Hebert et al., 2002). These
findings have led to the hypothesis that BMP signaling is required to form the
dorsal midline.
MATERIALS AND METHODS
Mice
Breeding and genotyping of Foxg1Cre,
Bmpr1afx/fx and Bmpr1b-/- mice have been
described previously (Hebert and
McConnell, 2000; Mishina et
al., 2002). Control embryos were
Foxg1Cre/+;Bmpr1afx/+;Bmpr1b-/+.
RNA in situ hybridization, TUNEL and immunolabeling
RNA in situ hybridization, TUNEL and immunolabeling were carried out on
10-12 µm cryosections from fresh frozen embryos. For RNA situ analysis,
sections were hybridized with 35S-labeled RNA probes as previously
described (Frantz et al.,
1994). Plasmids were used to make probes: Bmp4
(Jones et al., 1991),
Fgf8 (Crossley and Martin,
1995), Foxg1 (Tao and
Lai, 1992), Lhx2
(Rodriguez-Esteban et al.,
1998), Msx1 (A. W. Helms), Nkx2.1
(Shimamura et al., 1995),
Pax6 (Walther and Gruss,
1991), Wnts (Grove et al.,
1998), Gsh2 (Gsx2 - Mouse Genome Informatics)
(Hsieh-Li et al., 1995),
Sfrp2 (Rattner et al.,
1997), Ttr (gift of W. S. Blaner, Columbia University,
NY, USA), Rfx4-v3 (Blackshear et
al., 2003), Zic2 (gift of M. Hayhurst, Stanford
University, CA, USA), Actr1 (ATTC, Image Clone 5336738). TUNEL
analysis was performed according to the manufacturer's specifications (Roche,
catalog #2156792). Immunolabeling for phosphohistone H3 was performed with a
polyclonal (Upstate, 1:200) and a Texas Red-conjugated secondary antibody.
Cell counts and data analysis were performed as previously described
(Gutin et al., 2006).
|
The Bmpr1a;Bmpr1b double mutant is holoprosencephalic
To test the role of BMP signaling in telencephalon development, mouse
embryos lacking both Bmpr1a and Bmpr1b were generated using
the cross illustrated in Fig.
1A. Double-mutant embryos were obtained until E11.5 without signs
of necrosis. However, at this age, the expected ratio of double mutants
(6.25%) was not obtained (3.5% of 202 embryos), indicating some lethality. The
dorsomedial area of the E11.5 double-mutant telencephalon appeared rounded and
less defined, whereas a midline remained visible rostrally. Severe reduction
of the eyes was also observed (Fig.
1C). These phenotypes are 100% penetrant with essentially
invariable severity. RNA in situ hybridization analysis for the deleted
segment of Bmpr1a, as previously performed
(Hébert et al., 2002),
revealed that expression begins to disappear at E8.5 (10 somites) and is
absent by E9.5 in the telencephalon, whereas expression is unaffected in other
tissues, such as the head mesenchyme, foregut and heart (see Fig. S1 in the
supplementary material).
At E10.5 and E11.5, although a midline still formed rostrally in the mutant, it did not show the characteristic thinning observed in controls (Fig. 1D-E',H,I). More posteriorly in controls, the choroid plaque was identifiable as a thin neuroepithelium protruding inward from the dorsal midline creating the medial walls that separate the ventricles, whereas in the double mutant this thin inward protrusion failed to form, resulting in HPE (Fig. 1F-G',J,K). The worsening phenotype at E11.5 indicates that the phenotype observed at E10.5 is not due to a delay in midline development. Even more posteriorly, the diencephalon of the mutant was rounded and displaced, presumably owing to the lack of an invaginated dorsal telencephalic midline in which to intercalate (data not shown). These results indicate that disrupting BMP signaling prevents the formation of a morphologically defined dorsal midline and induces HPE.
Dorsal midline cell types fail to form in the Bmpr1a;Bmpr1b double mutant
The telencephalic dorsal midline is composed of the choroid plexus and the
cortical hem. The choroid plexus is marked at E11.5 and onward by the
expression of Ttr. In the double mutant, no Ttr-positive
cells were detected anywhere along the rostrocaudal axis of the telencephalic
dorsal midline (Fig. 2A,B).
From E10/E10.5 onward, Wnt2b and Wnt3a were strongly
expressed in the cortical hem (Grove et
al., 1998; Lee et al.,
2000). In the double mutant at E10.5 and E11.5, expression of
these genes was greatly diminished or absent throughout the rostrocaudal axis
(Fig. 2D and data not shown).
Moreover, the choroid plaque and cortical hem normally express Msx1
at E9.5 and 10.5. In the mutant, however, Msx1 expression was lost
(Fig. 2F and see Fig. S4 in the
supplementary material). These results demonstrate that BMP signaling is
required for formation of the choroid plexus and cortical hem.
Other markers that are also expressed in the medial area of the dorsal
telencephalon were, however, still readily detected in
Bmpr1a;Bmpr1b mutants. Bmp4 and Wnt8b,
whose expression at E10.5 normally extends beyond the choroid plaque and
cortical hem into the adjacent neuroepithelium, were still expressed in the
double mutant, although the length of the expression domain appeared
diminished, presumably owing to the loss of midline cell types
(Fig. 2G,H and data not shown).
Interestingly, Zic2, a gene implicated in forms of human and mouse
HPE in which the dorsal midline is lost
(Nagai et al., 2000), was
expressed in double mutants (Fig.
2I,J), demonstrating that BMP signaling is not required for the
maintenance of Zic2 expression.
From E9.5 onward, the midline is marked by high levels of apoptosis. In control E10.5 brains, TUNEL labeling was clearly visible at the dorsal midline, whereas in the double mutant no midline apoptosis was observed (Fig. 2K,L). This demonstrates that BMPR signaling is required in vivo for midline apoptosis in the telencephalon. Surprisingly, the double mutant also exhibited a loss of apoptosis in the rostroventral area of the midline. One potential explanation is that the strong dorsal expression of certain Bmp genes, such as Bmp4 and Bmp5, extends far enough through the rostral midline to act ventrally at E10.5 (Fig. 2G, arrow, and data not shown).
|
|
; Mehler et al.,
2000). Bmpr1a and Bmpr1b have also been
hypothesized to have opposing functions, with Bmpr1a promoting and
Bmpr1b inhibiting telencephalic precursor cell proliferation
(Panchision et al., 2001). In
the E10.5 Bmpr1a;Bmpr1b double mutant, no significant
changes in the percentage of mitotic (phosphohistone H3-positive) cells were
observed in medial or lateral areas (for pooled areas: control,
5.6±1.5% s.d.; mutant, 5.9±1.2%; P=0.6), suggesting
that at least at this age, BMP signaling is not required to regulate
proliferation. Overall, the phenotypes observed demonstrate functional overlap
between Bmpr1a and Bmpr1b in dorsal midline development.
Overexpression of a constitutively active BMPR1A transforms cortical
precursors into choroid plexus cells
(Panchision et al., 2001),
suggesting that BMP signaling has the potential to induce the choroid plexus
cell fate. Deletion of Bmpr1a, although demonstrating a requirement
for BMP signaling in choroid plexus development, failed to distinguish between
a requirement to induce precursor cells to adopt a choroid plaque fate or to
promote the differentiation of already specified precursors
(Hebert et al., 2002).
However, in the Bmpr1a;Bmpr1b double mutant, expression of
Msx1, a marker for both choroid plaque and cortical hem precursors,
was absent (Fig. 2E,F),
consistent with a failure to induce these cell types. The alternative
possibilities that BMP signaling is required to maintain proliferation or
survival of specified precursors are less likely because no change in these
processes was observed in the double mutant.
Cortical patterning is grossly normal in the double mutant
Compelling evidence suggests that BMPs pattern the cortical neuroepithelium
(Monuki et al., 2001;
Shimogori et al., 2004;
Hirabayashi et al., 2004;
Crossley et al., 2001;
Ohkubo et al., 2002;
Cheng et al., 2006;
Theil et al., 2002). To
address this hypothesis, we analyzed E10.5 and E11.5 double mutants for the
expression domains of transcription factors that specify cortical fates:
Lhx2, Foxg1, Emx2 and Pax6. Surprisingly, the expression of
these factors, normally present in cortical precursors and excluded or greatly
reduced in the dorsal midline, was not affected in the
Bmpr1a;Bmpr1b mutant
(Fig. 3A-D and data not shown).
This suggests either that BMP signaling does not regulate the expression of
these genes or that there is another signal, possibly Wnt8b (see
above) (Gunhaga et al., 2003),
that compensates. In embryos in which the dorsal midline is ablated (and thus
a primary source of both BMPs and WNTs is removed), the expression of
Emx2, Lhx2, Pax6 and Ngn2 (Neurog2) is also
maintained; although for Emx2 and Lhx2, their normal
gradients of expression are flattened
(Cheng et al., 2006). Subtle
changes in the slopes of expression gradients might not be detected with the
RNA in situ approach used here. Expression of the v3 variant of
Rfx4, which marks the dorsal telencephalon and is essential for
medial cortex and hem development
(Blackshear et al., 2003), also
appeared unperturbed in the double mutant (see Fig. S2 in the supplementary
material).
|
E8.5) is sufficient to convey grossly normal patterning to
cortical regions. Actr1, which encodes a type I receptor with
affinity for BMP2, 4, 6 and 7 (ten Dijke
et al., 2003; Derynck and
Zhang, 2003), was not expressed in the telencephalon until after
E10.5 (see Fig. S3 in the supplementary material and data not shown).
Nevertheless, the results presented here demonstrate that Bmpr1a and
Bmpr1b are not required for maintaining the domains of expression of
cortical transcription factors.
Ventral patterning is maintained in the Bmpr1a;Bmpr1b mutant
In most cases of HPE caused by a mutation in a known gene, ventral
telencephalic development is greatly impaired in mice and humans (e.g.
Shh mutants) (Muenke and Beachy,
2000; Hayhurst and McConnell,
2003; Chiang et al.,
1996). However, expression of Nkx2.1, Gli1 and
Fgf8, which depends on SHH signaling
(Ohkubo et al., 2002;
Pabst et al., 2000;
Park et al., 2000), and of
Shh, Gsh2 and Sfrp2 was maintained in the E10.5
Bmpr1a;Bmpr1b double mutant, although Fgf8
expression was lost in the rostral midline
(Fig. 3E-L and data not shown).
These results demonstrate that ventral cell specification is preserved in the
Bmpr1a;Bmpr1b mutant, unlike in other mouse models for HPE
(Muenke and Beachy, 2000;
Hayhurst and McConnell,
2003).
The dorsal midline initially forms in the Shh mutant
Although some dorsal midline features have been reported in the
Shh mutant (Ohkubo et al.,
2002), a more detailed examination of the dorsal midline in these
mutants is lacking. To examine the dorsal midline in Shh mutants,
expression of Msx1, Bmp5, Bmp4 and Foxg1 was analyzed at
E10.5. Msx1, Bmp5 and Bmp4 were still expressed in the
dorsal midline, whereas Foxg1 expression remained excluded
(Fig. 4C-H and data not shown).
Moreover, apoptosis was maintained (Fig.
4A,B). This indicates that the initial formation of the dorsal
midline occurs, unlike the HPE phenotype observed in the
Bmpr1a;Brmp1b mutant. Moreover, the lack of hemispheric
separation dorsally in the Shh mutant at E10.5 could at least in part
be due to a failure of the expansion of lateral areas, as compared with
control embryos (Fig. 4).
The present study demonstrates that mutations in the BMP pathway can lead to HPE with a lack of the dorsal midline. In contrast to the majority of HPE cases described in humans and mice, ventral patterning in Bmpr1a;Bmpr1b mutants is not affected and thus mimics the MIH subclass of HPE. These results support the existence of at least two developmental mechanisms leading to HPE: one involving loss of ventral medial cell types without a loss of early dorsal midline features, as in mutants in which the SHH pathway is disrupted; and a second involving a lack of dorsal midline development without impaired cell specification in the ventral telencephalon, as in the Bmpr1a;Bmpr1b mutant (Fig. 4I).
Note added in proof
Recent independent findings confirm the presence of early dorsal midline
features in the Shh-/- mutant mice
(Rash and Grove, 2007).
Supplementary material
Supplementary material for this article is available at
http://dev.biologists.org/cgi/content/full/134/21/3789/DC1
ACKNOWLEDGMENTS
This work was supported in part by the Sinsheimer Foundation, the James S. McDonnell Foundation, NIH MH075779 and MH70596 (to J.M.H.).
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