Cell Biology Program, Memorial SloanKettering Cancer Center, New York, NY 10021, USA
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Abstract |
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Introduction |
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The neurons and glia of the central nervous system (CNS) arise from the neuroepithelium of the neural plate. The neuroepithelium is comprised of pluripotent progenitor cells, which serve as the stem cells of the CNS. One of the most striking manifestations of regional differentiation along the neural tube is the greater expansion of the rostral end of the neural tube to form the brain. Differences are also apparent in the growth of subregions of the brain (Tuckett and Morris-Kay, 1985; Schoenwolf and Alvarez, 1989
). During evolution, the growth of the telencephalon has become progressively more prominent (Hofman 1989
). This has resulted in the disproportionate growth of the cerebral hemispheres in mammals and especially in primates. The differential growth of the neural tube is largely dependent on the proliferation of the progenitor cells within each region (Dehay et al., 1993
).
Early in development, neuroepithelial cells undergo symmetric cell divisions to give rise to daughter cells which continue to divide, thereby increasing the progenitor population. As development proceeds, the G1 phase of the cell cycle becomes progressively longer (Kaufman, 1968; Waechter and Jaensch, 1972
; Hoshino et al., 1973
), resulting in a slower rate of cell division. Secondly, the fraction of cells which withdraw from the cell cycle to initiate neuronal differentiation increases progressively. The size of the progenitor pool and hence the number of neurons generated from this pool depends both upon the number of cell divisions and the fraction of cells which exit the cell cycle after each mitosis (Caviness et al., 1995
). The larger size and the greater number of neurons found in the cerebral hemispheres compared to other regions of the brain can be attributed primarily to a prolonged period of progenitor cell proliferation which permits additional cell divisions. Within the cerebral cortex and other laminar structures of the brain, the time of neuronal differentiation, i.e. the birthdate, also determines the laminar fate of the neuron (Bayer and Altman, 1987
; McConnell, 1991
). Thus the mechanisms which control progenitor cell proliferation and regulate their progression through the cell cycle are of central importance in the development of the brain.
Tremendous progress has been made in recent years in understanding the basic machinery of the cell cycle. For most cells, entry into S phase from G1 is the critical regulatory step which determines whether the cell will proliferate or undergo differentiation or apoptosis. G1 progression is controlled by the activity of cyclin-dependent kinases and phosphatases which modulate the phosphorylation state of Rb and related proteins. The activity of these components of the cell cycle machinery can be regulated by extracellular signals, including mitogens and growth inhibitors. Despite the advances in understanding the molecular components of the cell cycle, very little is known about the control of the cell cycle during vertebrate development.
We have investigated the function of a winged-helix (WH) transcription factor, brain factor-1 (BF-1), in the development of the brain. WH proteins are a family of putative transcriptional regulators which have diverse roles in development (Lai et al., 1993; Kaufman and Knochel, 1996
). Members of this gene family were first identified in mammals as transcriptional activators of liver gene expression, the HNF-3 factors and in Drosophila as a nuclear protein, fkh, which was required for the development of head and tail structures in the embryo (Weigel et al., 1989
; Lai et al., 1990
, 1991
). This gene family is characterized by a highly conserved 100-amino acid DNA-binding domain, which, based on its structural features, was named the winged-helix domain (Clark et al., 1993
). Over 100 members of this gene family have now been identified in eukaryotes. Sequence homology outside of the WH domain is limited to short motifs shared among subgroups of the gene family. The function of other domains of these proteins has been poorly characterized to date. Most WH genes are expressed in the embryo and have important functions during development. Targeted disruption of a growing number of WH genes in mice result in developmental defects, suggesting important roles for these genes in patterning and morphogenesis. In this article, we will review the studies which establish the essential role of BF-1 in the development of the cerebral hemispheres and discuss its potential role in regulating cell cycle progression in the telencephalic neuroepithelium.
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Materials and Methods |
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Embryos were obtained from timed pregnancies, with noon of the plug date defined as embryonic day (E) 0.5. Embryos were fixed in 4% paraformaldehyde. E16.5 and older embryos were perfusion fixed by cardiac puncture. Paraffin embedding was performed by dehydrating embryos through ethanol and Histoclear (National Diagnostics) prior to immersion in paraplast (Fisher Scientific). Sections of 8 µm were stained with hematoxylin and eosin.
ß-Galactosidase (ß-gal) staining in 10 µm cryostat sections and whole embyros was performed as previously described (Bonnerot and Nicolas, 1993). Sections were stained for 218 h, and counterstained with Nuclear Fast Red. Whole embryos were stained for 30 min24 h. Heterozygote specimens were stained for twice as long as homozygote specimens to compensate for the number of copies of ß-gal. Selected stained whole embryos were subsequently embedded in paraffin for sectioning and counterstaining with Nuclear Fast Red.
In Situ Hybridization
Embryos were fixed in 4% paraformaldeyde and embedded in paraffin or in OCT (Miles) for frozen sections. Sections (8 µm) were processed for in situ hybridization with 33P-or digoxigenin-labeled probes as previously described except for the following changes (Tao and Lai, 1992; Schaeren-Wiemers and Gerfin-Moser, 1993
). Digoxigenin-labelled cRNA probes (15 nM) were hybridized at 58°C. Anti-digoxigenin antibody (Boehringer Mannheim) diluted to 1:5000 was incubated with the tissue overnight. Probe templates were kindly provided by E. Boncinelli, Emx-2 (Simeone et al., 1992
); P. Gruss, Pax-6 (Walther and Gruss 1991
); J. Rubenstein, Dlx-2 (Krauss et al., 1993
); B. Hogan, BMP-4 (Furuta et al., 1997
).
Bromodeoxyuridine Incorporation and Immunohistochemistry
Immunohistochemical detection of bromodeoxyuridine (BrdU) (Gratzner, 1982), and MAP-2 (Sigma) was performed as previously described (Xuan et al., 1995
). Sections were counterstained lightly with hematoxylin.
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Results |
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BF-1 was discovered by searching for novel WH genes expressed in the brain. Low-stringency hybidization of a rat brain cDNA library with a rat HNF-3a probe revealed several novel cDNAs, two of which had intriguing patterns of expression in the developing brain. BF-1 expression was restricted to the most rostral region of the neural tube. At E12.5 in the mouse, BF-1 is present in the neural progenitors of the telencephalon and absent from the rest of the neural tube. Interestingly, a second WH gene, BF-2, is found in the immediately adjacent region of the neural tube, the rostral diencephalon (Fig. 1). Comparison of BF-1 and BF-2 expression patterns demonstrated that each gene demarcated distinct regions of the neuroepithelium, with a sharp boundary between their expression domains matching the morphological boundary between the telencephalon and the diencephalon.
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BF-1 is Required for the Development of the Cerebral Hemispheres
To evaluate the function of BF-1 during brain development, we generated mice with a targeted deletion of the BF-1 gene (Xuan et al., 1995). By replacing the coding sequence of BF-1 with that of ß-gal, we are able to identify BF-1 expressing cells in the heterozygote and the equivalent population of cells in the BF-1 (/) mutant. ß-gal staining serves as a marker of the telencephalic progenitor cells.
Heterozygotes are healthy, fertile and morphologically indistinguishable from their wildtype littermates. Homozygous BF-1 (/) mutants survive to term but die within minutes of birth. Although the exact cause of death remains unclear, the mice die with uninflated lungs and respiratory failure. Examination of the newborn mice reveals striking hypoplasia of the cerebral hemispheres. The rest of the brain is unaffected. Sections through the brain of mid-gestation embryos (E12.5) show that the telencephalic vesicles are much smaller than normal and distorted in contour (Fig. 3A,B). To determine whether this defect was due to abnormal specification of the telencephalic neuroepithelium or abnormal growth, we studied earlier stages of development. At E9.5, heterozygote and mutant embryos displayed no significant differences in the size of the telencephalic vesicles (Fig. 3C
). By E10.5 however, the telencephalic vesicles in the homozygous mutant were distinctly smaller than those in heterozygotes (Fig. 3D
). These results demonstrate that BF-1 is not required for the specification and initial formation of the telencephalic vesicles but is essential for the later growth of the telencephalon.
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BF-1 Regulates the Proliferation and the Timing of Neuronal Differentiation in the Telencephalic Neuroepithelium
In order to determine the mechanisms by which BF-1 controls the growth of the telencephalon, we measured the rate of cell proliferation within the neuroepithelium by BrdU labeling (Gratzner 1982). Pregnant mice were injected with BrdU and killed 2 h later. At E9.5, the fraction of BrdU-labeled cells in the telencephalon of the BF-1
mutant is indistinguishable from that of normal embryos. However, by E10.5, we observe a dramatic reduction in BrdU-labeled cells in the ventral telencephalic neuroepithelium of the mutant (Xuan et al., 1995
). The dorsal telencephalic neuroepithelium of the BF-1 (/) mutant appears to proliferate normally for a longer period of time. However by E12.5, we observe areas of diminished BrdU labeling interspersed with areas of apparently normal fractions of labeled cells. An abnormally wide zone of cells is formed outside of the cerebral cortical ventricular zone which expresses microtubule-associated protein (MAP) 2 (Crandall et al., 1986
) and does not label with BrdU. MAP2 is an early marker of differentiating neurons. These results suggest that cells of the dorsal telencephalic neuroepithelium are prematurely leaving the cell cycle and differentiating (Fig. 4
). We also detect MAP2 expression within some regions of the telencephalic ventricular zone (tvz, Fig. 4G
). Normally, the withdrawl of neuroepithelial progenitor cells from the cell cycle is tightly coupled to their migration away from the ventricular zone. The expression of MAP2 within the telencephalic ventricular zone is therefore highly unusual and suggests disregulated timing of both neuronal differentiation and migration.
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Members of the TGF-ß family, most notably the BMPs, have been shown to play important roles in neural patterning (Hogan 1996). Neural induction is believed to be regulated through the inhibition of BMP4 activity by molecules such as noggin and chordin which bind to BMP4 (Piccolo et al., 1996
; Zimmerman et al., 1996
). Later in development, several BMPs have been shown to function in dorsalventral patterning of the spinal cord. BMPs appear to act by inhibiting the spread of ventralizing signals, such as that mediated by the secreted polypeptide sonic hedgehog (shh) (Liem et al., 1995
). The function of BMPs in the development of the forebrain is less well understood. A recent study by Hogan and colleagues provides evidence that BMPs may function in the developing forebrain to inhibit the proliferation of neural progenitors (Furuta et al., 1997
). They found that several BMPs are expressed in distinct patterns within the developing forebrain. BMP expression in the anterior neuroectoderm is first detected at the 5 somite stage. Receptors for BMP4 and 7 are also expressed in the ventricular zone as early as E9.5 in the telencephalic vesicles and throughout the neural tube by E12.5 (Dewulf et al., 1995
). Thus multiple BMPs and their receptors are present in the neuroepithelium of the forebrain during the period of neurogenesis. BF-1 and BMPs are initially coexpressed at E9.5 throughout the telencephalon. However, by E10.5, the expression domain of BMP4 becomes complementary to that of BF-1. BMP4 expression becomes localized to the dorsomedial telencephalon and the roof of the telencephalon, in those cells which cease to express BF-1. Furthermore, in vitro studies demonstrate that BMP4 inhibits the proliferation of the telencephalic neuroepithelium in explant cultures of the mouse forebrain as well as the expression of BF-1 (Furuta et al., 1997
). These observations suggest that BMPs may function in the regional inhibition of cell proliferation in the forebrain neuro epithelium.
Because the pattern of BMP expression in the forebrain becomes complementary to that of BF-1 by E10.5, we postulated that BF-1 might repress BMP expression. To test this possibility, we examined the expression pattern of BMP4 in theBF-1 (/) mutant and their normal heterozygous littermates. Figure 5 shows that the deletion of the BF-1 gene leads to ectopic expression of BMP4 in the telencephalon. At E11.5, instead of being restricted to a small region of the dorsomedial telencephalon, BMP4 expression is observed throughout the dorsal telencephalic neuroepithelium (Fig. 5D
). Expression of BMP4 is found to overlap the expression domain of the lacZ marker in the mutant, whereas in the heterozygote, BMP4 expression and BF-1 expression domains are complementary.
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Discussion |
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The potential role of BF-1 in regulating cell proliferation was first suggested by the observation that the avian sarcoma virus 31 encodes a WH gene, v-qin, which is highly homologous to BF-1 (Li and Vogt 1993). The cellular homolog of qin is believed to be the chick homolog of BF-1 based on its sequence similarity and its restricted pattern of expression in the chick telencephalon (Chang et al., 1995
). Overexpression of both the viral and cellular versions of qin was shown to induce oncogenic transformation of chicken embryo fibroblasts. The transforming activity of qin requires both the DNA binding domain and the C-terminal 48 amino acids (Chang et al., 1996). These studies suggest that BF-1 can function to regulate cell growth.
Insight into the physiological role of BF-1 in the developing embryo has come from the analysis of mice with a targeted deletion of the BF-1 gene. These studies provide further support for the hypothesis that BF-1 regulates cell proliferation. The loss of BF-1 leads to the failure of the cerebral hemispheres to grow normally. We observe reduced proliferation and premature differentiation of telencephalic progenitor cells in the BF-1 (/) mutant. The resulting early depletion of the progenitor cell population in the dorsal telencephalic neuroepithelium is likely to be the primary basis for the small size of the dorsal telencephalon in the BF-1 mutant. From these findings, we conclude that a major function of BF-1 during the period of neurogenesis is to delay the onset of neuronal differentiation in telencephalic progenitors. We postulate that BF-1 increases the number of neurons generated in the telencephalon by regulating the cell cycle specifically in the telencephalic progenitor population. These activities of BF-1 are restricted by its limited expression domain, providing a mechanism to control cell proliferation in a precisely defined population of progenitor cells. Ectopic expression of XBF-1 in the posterior neural plate results in the suppression of neuronal differentiation in Xenopus (Bourguignon et al., 1998). We speculate that the regional differences in the growth and expansion of the neural tube are determined by the combinatorial activity of multiple genes with restricted expression patterns in the neuroepithelium. A number of other WH transcription factors are expressed in different patterns within the neural tube, raising the possibility that other WH family members may have a function similar to that of BF-1 in other regions of the neuroepithelium.
What regulates the expression of BF-1? Recent studies have begun to address this question. Cells at the boundary between the anterior ectoderm and the anterior neural plate comprise the anterior neural ridge (ANR). Extirpation and transplantation studies in culture show that the ANR is required for the expression of BF-1 in the anterior neural plate. FGF8 is present in the ANR at the 4 somite stage (Crossley and Martin, 1995). In explants, FGF8 is able to substitute for the activity of the ANR to induce the expression of BF-1 in neural tissue. These observations suggest that FGF8 may play a role in the initiation of BF-1 expression (Shimamura and Rubenstein 1997
; Ye et al., 1998
). The restriction of BF-1 expression may also be controlled by extracellular signals. Application of exogenous BMP4 to fore-brain explants results in the downregulation of BF-1 expression in the telencephalic neuroepithelium (Furuta et al., 1997
). In contrast, the ectopic expression of BMP4 in the telencephalic neuroepithelium of the BF-1 mutant does not lead to the repression of the BF-1 promoter as measured by the expression of the lacZ marker. This discrepancy may be accounted for by differences in the levels of BMP4 protein. In the explant studies, the inhibition of BF-1 expression is observed only in a well-demarcated ring of cells surrounding the BMP4-soaked bead, suggesting a requirement for a certain threshold of BMP4 signal.
BF-1: A Modulator of Growth Regulators?
How does BF-1 regulate the proliferation of telencephalic progenitors during development? One possibility is that BF-1 directly stimulates cell proliferation, by regulating the expression of genes involved in cell cycle control. For example, BF-1 could enhance the expression of the components of the cell cycle machinery which promote G1 to S progression. However, we have not found any alterations in the expression of G1 cyclins and cdks in the BF-1 (/) mutant. In addition, although BF-1 is normally present in the telencephalic neuroepithelial cells by E8.0, the loss of BF-1 has no demonstrable effect on neuroepithelial cell proliferation until E10.5 in the ventral telencephalon and until E11.5 days in the dorsal telencephalon. Futhermore, telencephalic progenitor cells are able to withdraw from the cell cycle and differentiate despite the continued expression of BF-1 in these cells. These findings suggest that the regulation of cell proliferation by BF-1 is dependent on other factors. We hypothesize that BF-1 functions as a modulator of growth regulatory signals. Neuroepithelial cells in the embryo are exposed to multiple extracellular signals which regulate their fate, including fibroblast growth factors, Wnt proteins, transforming growth factor ß related factors and shh. We propose that BF-1 regulates the balance between proliferation and growth arrest, by controlling the expression of these signals or the response of the progenitor cells to them. We have found that the loss of BF-1 leads to ectopic expression of BMP4 in the telencephalic neuroepithelium. This result demonstrates that BF-1 is required for the downregulation of BMP4 from the dorsal telencephalon. Taken together with the prior demonstration that BMP4 inhibits telencephalic progenitor cell proliferation in explant cultures, our findings raise the possibility that the ectopic expression of BMP4 leads to premature differentiation in the dorsal telencephalon. However, there is a caveat to this interpretation. In explant cultures, BMP4 was also shown to inhibit BF-1 expression in the same cells which were growth inhibited. The expression of the lacZ marker in the BF-1 mutant is not altered, indicating that BF-1 promoter activity is not suppressed as a consequence of the ectopic expression of BMP4. This result may suggest a requirement for BF-1 in the activity of BMP4 or alternatively that the level of ectopic BMP4 protein present in the BF-1 (/) mutant is not comparable to the levels achieved in vitro. Thus, the biological significance of ectopic BMP4 expression in the BF-1 (/) mutant will require further examination. A recent study in Xenopus suggests that BF-2 may also function as a repressor of BMP expression (Mariani, 1998).
Role of BF-1 in DorsalVentral Patterning of the Telencephalon
The analysis of the BF-1 (/) mutant mice has revealed an unanticipated function of BF-1 in the patterning of the telencephalon along the dorsalventral axis. The loss of BF-1 results in the expansion of dorsal cell fate at the expense of ventral cell fates. This observation invites comparison with the phenotype of the shh mutant mouse. Deletion of the 1800
shh gene leads to the formation of a single forebrain vesicle, which lacks ventral cell fates. The dorsal marker, Emx2 expression, is detected throughout the single telencephalic vesicle. Although the BF-1 (/) mutant also lacks expression of ventral markers in the telencephalon, it differs from the shh mutant in that the expression of emx2 is excluded from the ventral region. We interpret this to suggest that the initial specification of the ventral telencephalic neuroepithelium still occurs in the BF-1 (/) mutant. We postulate that this initial specification is the result of shh activity from the rostral diencephalic neuroepithelium and/or the rostral mesendoderm, both of which are unaltered in the BF-1 (/) mutant. The domain of shh expression which is normally induced in the ventral telencephalic neuroepithelium after E9.5 is not detected in the BF-1 (/) mutant. This deficit is associated with the loss of the expression of ventral markers, Dlx-2 and Nkx2.1, as well as a more pronounced proliferation defect in the ventral telencephalon. shh has been shown to be capable of inducing nkx2.1 in the anterior neural plate (Shimamura and Rubenstein, 1997). We speculate that the localized loss of shh activity in the telencephalon of the BF-1 mutant underlies the defects in ventral cell differentiation. shh has been demonstrated to have mitogenic activity for many cell types. The loss of shh could therefore also contribute to the more severe proliferation defect in the ventral telencephalon of the BF-1 (/) mutant.
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Summary |
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Notes |
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Address correspondence to Chang-Lin Dou, Cell Biology Program, Box 83, Memorial SloanKettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. Email: c-dou{at}ski.mskcc.org.
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References |
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