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Journal of Dental Research
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Biological

Identification of Cis-DNA Regions Controlling Bmp4 Expression during Tooth Morphogenesis in vivo

J.Q. Feng*,1, J. Zhang1, X. Tan, Y. Lu, D. Guo and S.E. Harris

School of Dentistry, Dept. of Oral Biology, University of Missouri-Kansas City, 650 E. 25th St., Kansas City, MO 64108;

Correspondence: * corresponding author, fengj{at}umkc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS & MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epithelial-mesenchymal interactions are required for tooth formation. Bone morphogenetic protein 4 (Bmp4) is a crucial signaling molecule during this process. For better understanding of the role of the Bmp4 gene during tooth development, we studied the mechanisms that control its temporal and spatial expression during development. Using a transgenic approach, we determined that the domains which controlled Bmp4 expression in epithelium-derived ameloblasts were located in the region between 0.26 kb and 1.1 kb of the murine Bmp4 promoter. In contrast, the domains controlling Bmp4 expression in mesenchyme-derived odontoblasts and pulp cells existed in other regions of the Bmp4 gene. We have also demonstrated that the domains controlling Bmp4 expression in primordial tooth cells differ from those controlling Bmp4 expression in mature tooth tissues. The determination of unique domains by controlling the expression of the Bmp4 gene suggests that different transcriptional factors regulate the Bmp4 level at different stages during tooth morphogenesis.

Key Words: Bmp4 • transgenic mice • tooth • development • promoter


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS & MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sequential and reciprocal epithelial-mesenchymal interactions initiate murine tooth formation (Thesleff and Sharpe, 1997). The first morphological sign of tooth development is a thickening of the oral ectoderm, referred to as dental epithelium. The dental epithelium invaginates further into the underlying ectomesenchyme and eventually differentiates into enamel-forming ameloblasts. As these morphologic changes occur, the underlying ectomesenchymal cells condense around the dental epithelium. The condensed mesenchyme differentiates into the dental papilla and gives rise to the tooth pulp and the dentin-producing odontoblasts.

Bone morphogenetic protein 4 (Bmp4) is an essential growth factor for embryo development, because it plays a significant role in a large number of developmental systems, such as branching morphogenesis of the lung, lens development, neuroepithelial cell differentiation, primordial germ cell formation, and hair, whisker, and feather formation (Hogan, 1996, 1999; Furuta and Hogan, 1998; Jung et al., 1998; Noramly and Morgan, 1998; Oro and Scott, 1998; Lawson et al., 1999). Recent evidence also suggests that Bmp4 is crucial for tooth formation. First, Bmp4 is expressed in dental epithelium during the initiation of tooth development. Shortly afterward, in the early bud stage, the expression shifts to the dental mesenchyme (Chen and Maas, 1998). This shift of the Bmp4 expression pattern is consistent with the known pattern of sequential and reciprocal epithelial-mesenchymal interactions (Thesleff and Sharpe, 1997). Second, in vitro application of recombinant Bmp4 to the dental mesenchyme mimics the action of dental epithelium during the induction of tooth development. This includes both the morphological changes and the expression of several genes such as Msx1, Msx2, Lef1, and Bmp4 itself (Vainio et al., 1993; Chen et al., 1996; Kratochwil et al., 1996; Thesleff and Sahlberg, 1996). Third, exogenous Bmp4 can partially rescue arrested tooth development in Msx1 mutant mice. These mice display an early arrest of tooth formation and a marked reduction of Bmp4 in the molar mesenchyme (Satokata and Maas, 1994; Chen et al., 1996). Finally, Bmp4 has been linked to determining the sites of tooth development, as well as the type of tooth formed (Neubüser et al., 1997; Tucker et al., 1998).

Understanding the mechanisms underlying the pattern of the temporal and spatial expression of Bmp4 is essential for the identification of the transcriptional factors that are involved in Bmp4 regulation during development. Therefore, we cloned the murine Bmp4 gene, partially characterized its promoter region (Feng et al., 1995), and demonstrated that the domains controlling Bmp4 expression in primordial hair tissues differed from those of mature hair follicles (Feng et al., unpublished observation). Also, the domains controlling Bmp4 expression in hair shaft, hair matrix, and dermal papilla are located in different regions of the Bmp4 gene. The purpose of this study was to determine the extent to which the promoter domains controlling Bmp4 expression in primordial murine teeth were the same as those controlling Bmp4 expression in mature tooth tissues. In addition, we sought to determine if the domains controlling Bmp4 expression during tooth morphogenesis were specific for particular cell types such as odontoblasts or ameloblasts, or for specific types of teeth such as incisors or molars. Using transgenic mice carrying a β-galactosidase (lacZ) reporter gene driven by different promoter fragments, we have identified a promoter region between –0.26 kb and –1.1 kb of the murine Bmp4 gene that controls its expression in epithelium-derived ameloblasts. We have also demonstrated that regions controlling Bmp4 expression in primordial tooth tissues are different from those controlling its expression in mature teeth.


   METHODS & MATERIALS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS & MATERIALS
RESULTS
 DISCUSSION
 REFERENCES
 
Bmp4lacZneo Mice
The Bmp4lacZneo mouse line was a kind gift from Ray Dunn and Brigid Hogan of Vanderbilt University, Nashville, TN. An abbreviated diagram of the Bmp4 LacZ knock-in construct is presented in the lower panels of Figs. 1 and 3GoGo. An NLS-lacZ pA-neomycin cassette replaces most of exon three of the mouse Bmp4 gene. The pattern of lacZ expression in these mice is a sensitive reflection of expression of the entire endogenous Bmp4 gene and reflects the entire cis-regulatory system (Lawson et al., 1999).


Figure 1
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  		Figure 1. LacZ is strongly expressed during early tooth morphogenesis in Bmp4lacZneo knock-in mice, while LacZ expression in transgenic mice harboring the 2.4-kb Bmp4 promoter LacZ (Bmp4 LacZ 2.4p) construct is absent when evaluated at the same developmental stages. (A) Stage E11.5 whole-mount embryos from heterozygous Bmp4lacZneo knock-in (left panel) and Bmp4LacZ2.4p (right panel) mice were stained for β-galactosidase activity overnight. Note that expression signals in the somites are similar in Bmp4lacZneo knock-in mice and Bmp4LacZ2.4p mice, although the expression levels are different. A series of frozen sections from early incisor tooth buds from E12.5 (B), E13.5 (C), and E15.5 (D) embryos was stained with x-gal. A schematic construct map is displayed in the lower panels. Expression of LacZ in mice harboring the Bmp4lacZneo knock-in construct, in which the NLS-LacZ-neo cassette replaces part of Exon3 in the mouse Bmp4 gene, is a sensitive indicator of endogenous Bmp4 expression. Abbreviations: E, epithelium; M, mesenchyme; DF, dental follicle; DO, dental organ; DP, dental papilla. The data shown are representative of three separate experiments in the same developmental stages.

 

Figure 3
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  		Figure 3. The 1.1-kb Bmp4 gene region contains the control domains for Bmp4 expression in the epithelium-derived ameloblast. Sections of molars from newborn Bmp4lacZneo knock-in (A, labeled Bmp4LacZknock-in) mice, Bmp4LacZ2.4p (B), and Bmp4LacZ1.1p (C) mice were stained by the β-galactosidase antibody (green). A white arrow indicates the odontoblast layer in each panel, while a red one designates the ameloblast layer. Schematic presentation of the Bmp4 LacZ constructs is shown in the lower panels. Bmp4 promoter fragments –2372 to +258 (2.4 kb) and the -1140 to +212 (1.1 kb) are used to generate Bmp4LacZ2.4p and Bmp4LacZ1.1p mice. Abbreviations: Am, ameloblast; Od, odontoblast. The data shown are representative of three separate experiments in the same developmental stages.

 
Mouse Bmp4 Promoter-lacZ Constructs
Three fragments of the Bmp4 1A promoter and part of the 5'–exon 1 (the -2372/+258, the -1140/+212, and the –260/+212) were inserted in front of pUC19/AUG β-gal containing the lacZ gene (Cheng et al., 1993). The transgenes of the -2372/+258-lacZ and the -1140/+212-lacZ were released from the backbone vectors by means of Hind III and Pst I, and the transgene of the –260/+212 lacZ was released by means of Hind III and BamHI. All digested DNA fragments were isolated from agarose gels, and purified with Qiagen columns (Valencia, CA, USA). A schematic construct map is displayed in the lower or right panels of Figs. 1, 2, and 3GoGoGo.


Figure 2
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  		Figure 2. Bmp4 LacZ expression in mesenchyme-derived pulp cells and odontoblasts is absent in Bmp4LacZ2.4p mice. Sagittal sections from the head region of newborns were stained for β-galactosidase activity. The upper panels are from Bmp4LacZ2.4p mice, while the lower panels are from Bmp4lacZneo knock-in mice. Schematic construct maps are displayed in the right panels. LacZ expression patterns in Bmp4lacZneo knock-in and Bmp4LacZ2.4p mice are the same in all incisors and molars. Abbreviations: Am, ameloblast; Od, odontoblast; P, pulp cells. Note that the construct used in Bmp4LacZknock-in mice contains nuclear localization signal peptide; thus, the expressed β-galactosidase is mainly in the nucleus. The data shown are representative of four separate experiments.

 
Generation of Transgenic Mice
For the production of Bmp4-LacZ transgenic mice, the lacZ reporter gene driven by a mouse Bmp4 promoter fragment (either the -260/+212, the -1140/+212, or the –2372/+258) was injected into fertilized eggs at a DNA concentration of 3 ng/µL. The fertilized eggs were obtained from superovulated BL6CBAF1/J (C57BL/6J x CBA/J). Surviving eggs were transferred into the oviducts of pseudopregnant CD-1 recipient mice to obtain transgenic mice expressing the lacZ gene driven by each Bmp4 promoter fragment. Tail DNAs from offspring were used to identify transgenic mice (described below). The copy number of the transgene was determined by Southern blotting. The animal-use protocol was reviewed and approved by the Institutional Animal Care and Use Committee of the University of Missouri at Kansas City.

β-Galactosidase Expression Assay and Immunostaining
b-galactosidase staining was assessed in embryos and newborns according to the method described by Lawson et al. (1999). Briefly, embryos or newborns were fixed with 4% paraformaldehyde for 30 min on ice, and then washed 3 times with PBS for 5 min each. The specimens were then stained overnight in freshly made X-Gal solution (1 mg/mL) at 32°C. β-galactosidase immunostaining of sections was based on the method described by Liu et al. (1999). Both rabbit anti-lacZ antibody and goat anti-rabbit secondary antibody were obtained from Molecular Probes (Eugene, OR, USA).

Tail PCR Assay
The genotypes of pups were determined by PCR analysis of genomic DNA extracted from tail DNA. Primer 1 (5'-TCTGCTTCAATCAGCGTGCC-3') and anti-sense primer 2 (5'-GCCGTCTGAA TTTGACCTGA-3') were used to identify the lacZ gene.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS & MATERIALS
 RESULTS
DISCUSSION
 REFERENCES
 
Bmp4 LacZ Signals are Highly Active during the Entire Process of Tooth Formation.
To examine the onset of endogenous Bmp4 expression during tooth bud formation, we analyzed heterozygous Bmp4lacZneo knock-in embryos from stage E11.5 to newborns for β-gal activity. As shown in whole-mount staining at stage E11.5 (Fig. 1AGo), initial LacZ signals reflecting the endogenous Bmp4 expression pattern are evident in somites, limb buds, and guts, as well as the cranial-facial region. This suggests that Bmp4 is an early gene that is linked to the formation of many organ systems.

Specifically, the Bmp4 LacZ signal was observed in oral ectoderm at E12.5 (Fig. 1BGo), followed by the neural-crest-derived mesenchyme at E13.5 (Fig. 1CGo). By stage E15.5 (Fig. 1DGo), Bmp4 LacZ signals are highly active in dental follicles, dental organs, dental papilla, and enamel knots. At later differentiation stages, Bmp4 LacZ is expressed in both epithelium-derived ameloblasts, mesenchyme-derived tissues such as odontoblasts, and pulp cells (Figs. 2A, 3AGoGo). It is noteworthy that Bmp4 expression in pulp cells has not been reported before. This is probably due to the fact that the β-galactosidase inserted into the Bmp4 gene is a highly sensitive expression system. The weak Bmp4 signals in tooth pulp were not detected by in situ hybridization. Bmp4 expression in pulp cells, the odontoblast precursor cells, suggests potential roles of Bmp4 in dentin repair during post-natal life. In addition, Bmp4 expression patterns are very similar in both maxilla and mandible, as well as incisors and molars (Figs. 2, 3GoGo). Analysis of the data suggests that Bmp4 is actively involved in the entire process of tooth morphogenesis, first in the epithelial layer, then in the mesenchyme, and later in all mature tooth tissues, including ameloblasts, odontoblasts, and pulp cells.

The 2.4-kb Murine Bmp4 Promoter is Active in Epithelium-derived Ameloblasts, But Not in Mesenchyme-derived Odontoblasts or Primordial Tooth Tissues
To identify promoter regions controlling Bmp4 expression at different developmental stages and anatomical regions during tooth development, we analyzed LacZ expression in transgenic mice harboring the 2.4-kb Bmp4 promoter LacZ (Bmp4 LacZ2.4p) construct. LacZ expression in these mice was compared with LacZ expression in Bmp4lacZneo knock-in mice at the same developmental stages. As shown in Figs. 2-4GoGoGo, LacZ staining is apparent only in the epithelium-derived ameloblast (Figs. 2, 3GoGo), there is no LacZ expression in the mesenchyme-derived odontoblasts or pulp cells, and the pattern of Bmp4 expression is similar in both incisors and molars (Figs. 2, 3GoGo). It is critical to note that while the LacZ signals in somites are similar in Bmp4lacZneo knock-in and Bmp4 LacZ2.4p mouse embryos, there is little LacZ expression during the early stages of tooth morphogenesis (Fig. 1Go). This suggests that the domains controlling Bmp4 expression in somites, the primordial tissues for vertebral bone formation, differ from those controlling Bmp4 expression in primordial tooth tissues. Last, Bmp4LacZ signals are detected in tissues such as the tongue, nasal cartilages, bone, and small salivary glands (Figs. 2D, 2GGoGo), while the expression of the LacZ transgene driven by the 2.4-kb promoter fragment is absent in these tissues. This difference may be due to missing control domains or enhancers in the truncated promoter fragment.


Figure 4
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  		Figure 4. Temporal and spatial expression of Bmp4 during tooth development is controlled by different domains of the Bmp4 gene. The upper panel depicts a schematic of the working hypothesis for control of Bmp4 expression during tooth development. Supporting data show that LacZ staining in Bmp4lacZneo knock-in mice, representative of endogenous Bmp4 expression, first appears in the epithelium (A, 200x), followed by the mesenchyme and enamel knot (B, 200x), and then in the mature tooth cells such as pulp cells (C, 200x), odontoblast, and ameloblast cells (D, 40x). By contrast, panel E shows that LacZ stains from the Bmp4LacZ2.4p mice are present only in the epithelium-derived ameloblasts. We propose that the Bmp4 gene region from –260 bp to –1.1 kb controls Bmp4 expression in the epithelium-derived ameloblasts, while Bmp4 expression in the mesenchyme-derived pulp cells and odontoblast cells is controlled by other regions. The control domains for Bmp4 expression in primordial tooth cells (PTC, see Fig 1Go for more support data) are located in other regions of the Bmp4 gene, outside of the 2.4-kb Bmp4 gene area. Abbreviations: Am, ameloblast; Od, odontoblast; P, pulp cells.

 
The Activity of the 1.1-b Bmp4 Promoter is Similar to That of the 2.4-kb Bmp4 Promoter
To define further the control regions of the Bmp4 promoter, we compared LacZ expression in transgenic mouse lines containing lacZ driven by the 1.1-kb promoter fragment with lacZ expression in Bmp4lacZneo knock-in mice and Bmp4lacZ2.4p mice. Bmp4 LacZ1.1P, like Bmp4lacZ2.4p, is active in ameloblasts, but not in odontoblasts or in pulp cells (Fig. 3Go). In addition, this 1.1-kb fragment is not active in either the epithelium or the mesenchyme of early tooth buds (data not shown). This pattern of lacZ expression is similar to that observed in the Bmp4 LacZ2.4p mice described above. The 0.26-kb basic promoter region was tested with the same LacZ cassette (Bmp4lacZ.26P). In two independent lines, we saw no LacZ expression at any stage. These observations demonstrate that the region between -1140 and -260 of the Bmp4 gene contains the DNA cis-regulatory elements for controlling Bmp4 expression in epithelium-derived ameloblasts during stages of tooth differentiation.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS & MATERIALS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we document that both the 1.1-kb and the 2.4-kb murine Bmp4 promoters are sufficient to drive expression of an exogenous reporter gene in the epithelium-derived ameloblast layer. This expression pattern is similar to that of endogenous Bmp4 expression as determined by LacZ expression in Bmp4lacZneo knock-in mice, although the expression level in Bmp4lacZneo knock-in mice is stronger than that in Bmp4 LacZ2.4p mice. The difference in expression levels is most likely due to lack of enhancer(s) in the 2.4-kb promoter. By contrast, the –260 to +212 fragment has no in vivo promoter activity (data not shown). Thus, the domains controlling Bmp4 expression in the epithelium-derived ameloblast layer are present in the promoter region between 0.26 kb and 1.1 kb of the Bmp4 gene. It is noteworthy that this expression pattern is similar during the development of both the incisor and the molar (Figs. 2, 3GoGo). Also, the Bmp4 expression pattern is the same in both maxilla and mandible during tooth formation. Analysis of these data suggests that the control domains are specific for the particular type of tissues, rather than for anatomical location. These findings are in agreement with the expression pattern for Bmp4 during hair follicle morphogenesis (Feng et al., unpublished observation), in which the Bmp4 proximal promoter directs reporter gene expression in the epithelium-derived tissues, such as hair shaft and hair matrix, but not in the mesenchyme-derived dermal papilla. By contrast, promoter domains controlling Bmp5 (another member of the Bmp family) expression are specific for anatomical locations, rather than for particular types of tissues (DiLeone et al., 1998, 2000). For instance, the domains regulating Bmp5 expression in the upper region of the sternum differ from those for the lower region, and mutation of the 3' flanking domain of the Bmp5 gene disrupts expression in specific subsets of skeletal structures, rather than in all skeletal elements in which Bmp5 is normally expressed.

Also, we demonstrate that the Bmp4 domains controlling Bmp4 expression in primordial tooth tissues are different from those controlling its expression in mature tooth tissues. While there is strong LacZ expression in Bmp4lacZneo knock-in mice in both primordial tissues. such as the epithelium and the mesenchyme, and the mature tissues, including pulp cells, odontoblasts, and ameloblasts, there is little LacZ expression in primordial tissues from Bmp4LacZ2.4p mice (Fig. 1Go). Thus, we propose that domains controlling Bmp4 expression in primordial tooth buds and mature tooth tissues are different (see Fig. 4Go for detail). However, we do not have evidence to support a global model to fit other organ morphogenesis such as lungs, kidneys, and buds, because the activity of both the 1.1-kb and the 2.4-kb promoter fragments are too low for analysis of the transgene expression patterns in other organs. Last, the 2.4-kb promoter is active in somites while silent in primordial tooth tissues. This observation suggests that early transcriptional factors for controlling Bmp4 expression in somites are likely different from those for Bmp4 expression in primordial tooth tissues.

In summary, the current working hypothesis for Bmp4 control of tooth morphogenesis may aid in the understanding of the mechanics of epithelial-mesenchymal interactions that are initial steps in the development of many organ systems.


   ACKNOWLEDGMENTS
 
The authors acknowledge Dr. David L. Carnes, Department of Periodontics, UTHSC-San Antonio, for assistance during the preparation of this manuscript. We also thank N. Ray Dunn and Brigid Hogan for providing the Bmp4lacZneo knock-in mouse. This work was supported by NIH with grants to J.Q. Feng, DE13480, and to S.E. Harris, AR44728.


   FOOTNOTES
 
1 both authors contributed equally to this work; Back

Received for publication May 18, 2001. Revision received November 16, 2001. Accepted for publication November 27, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS & MATERIALS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Journal of Dental Research, Vol. 81, No. 1, 6-10 (2002)
DOI: 10.1177/154405910208100103
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