Expression patterns of bone morphogenetic proteins (Bmps) in the developing mouse tooth suggest roles in morphogenesis and cell differentiation

Bone morphogenetic proteins (BMP) are secretory signal molecules which have a variety of regulatory functions during morphogenesis and cell differentiation. Teeth are typical examples of vertebrate organs in which development is controlled by sequential and reciprocal signaling between the epithelium and mesenchyme. In addition, tooth development is characterized by formation of mineralized tissues: the bone‐like dentin and cementum as well as epithelially derived enamel. We have performed a comparative in situ hybridization analysis of the expression of six different Bmps (Bmp‐2 to Bmp‐7) starting from initiation of tooth development to completion of crown morphogenesis when dentine and enamel matrices are being deposited. Bmps‐2, ‐4, and ‐7 were frequently codistributed and showed marked associations with epithelial‐mesenchymal interactions. Their expression shifted between the epithelium and mesenchyme starting from the stage of tooth initiation. They were subsequently expressed in the enamel knot, the putative signaling center regulating tooth shape. Their expression domains prior to and during the differentiation of the dentine‐forming odontoblasts and enamel‐forming ameloblasts was in line with functions in regulation of cell differentiation and/or secretory activities of the cells. The expression of Bmp‐3 was confined to mesenchymal cells, in particular to the dental follicle cells which give rise to the cementoblasts, forming the hard tissue covering the roots of teeth. Bmp‐5 was expressed only in the epithelial ameloblasts. It was upregulated as the cells started to polarize and intense expression continued in the secretory ameloblasts. Bmp‐6 was expressed only weakly in the dental mesenchyme during bud and cap stages. Our results are in line with regulatory functions of Bmps at all stages of tooth morphogenesis. Bmps‐2, ‐4, and ‐7 are conceivably parts of signaling networks regulating tooth initiation and shape development. They as well as Bmp‐5 may be involved in the induction and formation of dentine and enamel, and Bmp‐3 in the development of cementum. The remarkable overlaps in the expression domains of different Bmp genes may implicate functional redundancy and/or formation of active heterodimers between different BMPs. Dev. Dyn. 1997;210:383–396. © 1997 Wiley‐Liss, Inc.

[1]  S. Keränen,et al.  The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. , 1998, Development.

[2]  E. Robertson,et al.  Overlapping expression domains of bone morphogenetic protein family members potentially account for limited tissue defects in BMP7 deficient embryos , 1997, Developmental dynamics : an official publication of the American Association of Anatomists.

[3]  K. Miyazono,et al.  Bone morphogenetic protein receptors. , 1996, Bone.

[4]  T. Ikeda,et al.  Transcripts for two members of the transforming growth factor‐β superfamily BMP‐3 and BMP‐7 are expressed in developing rat embryos , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[5]  V. Rosen,et al.  Identification of ovarian granulosa cells as a novel site of expression for bone morphogenetic protein-3 (BMP-3/osteogenin) and regulation of BMP-3 messenger ribonucleic acids by chorionic gonadotropin in cultured human granulosa-luteal cells. , 1996, The Journal of clinical endocrinology and metabolism.

[6]  R. Maas,et al.  Msx1 controls inductive signaling in mammalian tooth morphogenesis. , 1996, Development.

[7]  B. Hogan,et al.  Bone morphogenetic proteins: multifunctional regulators of vertebrate development. , 1996, Genes & development.

[8]  B. Hogan,et al.  Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis. , 1996, Development.

[9]  L. Niswander,et al.  Requirement for BMP Signaling in Interdigital Apoptosis and Scale Formation , 1996, Science.

[10]  J. Smith,et al.  Bone morphogenetic protein-4 (BMP-4) acts during gastrula stages to cause ventralization of Xenopus embryos. , 1996, Development.

[11]  B. Blumberg,et al.  Disruption of BMP signals in embryonic Xenopus ectoderm leads to direct neural induction. , 1995, Genes & development.

[12]  K. Lyons,et al.  A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. , 1995, Genes & development.

[13]  F. Luyten,et al.  Expression pattern of osteogenic protein-1 (bone morphogenetic protein-7) in human and mouse development. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[14]  H. Lesot,et al.  Induction of odontoblast-like cell differentiation in dog dental pulps after in vivo implantation of dentine matrix components. , 1995, Archives of oral biology.

[15]  P. Thorogood,et al.  Bone morphogenetic protein-2 and -4 expression during murine orofacial development. , 1995, Archives of oral biology.

[16]  B. Hogan,et al.  Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. , 1995, Genes & development.

[17]  R. Derynck,et al.  Vgr-1/BMP-6 induces osteoblastic differentiation of pluripotential mesenchymal cells. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[18]  M. Goumans,et al.  Expression of type I and type IB receptors for activin in midgestation mouse embryos suggests distinct functions in organogenesis , 1995, Mechanisms of Development.

[19]  K. Miyazono,et al.  Distinct spatial and temporal expression patterns of two type I receptors for bone morphogenetic proteins during mouse embryogenesis. , 1995, Endocrinology.

[20]  A. Aono,et al.  Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer. , 1995, Biochemical and biophysical research communications.

[21]  B. Hogan,et al.  Colocalization of BMP 7 and BMP 2 RNAs suggests that these factors cooperatively mediate tissue interactions during murine development , 1995, Mechanisms of Development.

[22]  A. Vaahtokari,et al.  Regulation of organogenesis. Common molecular mechanisms regulating the development of teeth and other organs. , 1995, The International journal of developmental biology.

[23]  A. Graham,et al.  The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest , 1994, Nature.

[24]  R. Derynck,et al.  Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo , 1994, The Journal of cell biology.

[25]  M. Nakashima.  Induction of Dentin Formation on Canine Amputated Pulp by Recombinant Human Bone Morphogenetic Proteins (BMP)-2 and -4 , 1994, Journal of dental research.

[26]  I. Thesleff,et al.  Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. , 1994, The International journal of developmental biology.

[27]  M. Loriot,et al.  Comparative analysis of TGF beta s, BMPs, IGF1, msxs, fibronectin, osteonectin and bone sialoprotein gene expression during normal and in vitro-induced odontoblast differentiation. , 1994, The International journal of developmental biology.

[28]  F. Luyten,et al.  Developing human lung and kidney are major sites for synthesis of bone morphogenetic protein-3 (osteogenin). , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[29]  N. Copeland,et al.  Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily , 1994, Nature.

[30]  R. Maas,et al.  Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development , 1994, Nature Genetics.

[31]  K. Heikinheimo.  Stage-specific Expression of Decapentaplegic-Vg-related Genes 2, 4, and 6 (Bone Morphogenetic Proteins 2, 4, and 6) During Human Tooth Morphogenesis , 1994, Journal of dental research.

[32]  A. Reddi,et al.  Initiation and promotion of bone differentiation by bone morphogenetic proteins , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[33]  I. Thesleff,et al.  Identification of BMP-4 as a signal mediating secondary induction between epithelial and mesenchymal tissues during early tooth development , 1993, Cell.

[34]  F. H. White,et al.  Bovine bone morphogenetic protein-induced dentinogenesis. , 1993, Clinical orthopaedics and related research.

[35]  R. Rutherford,et al.  Induction of reparative dentine formation in monkeys by recombinant human osteogenic protein-1. , 1993, Archives of oral biology.

[36]  F. Hoffmann,et al.  Drosophila transforming growth factor beta superfamily proteins induce endochondral bone formation in mammals. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  W. Gelbart,et al.  Human BMP sequences can confer normal dorsal-ventral patterning in the Drosophila embryo. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[38]  B. Hogan,et al.  Transgenic mice as a model to study the role of TGF-beta-related molecules in hair follicles. , 1993, Genes & development.

[39]  M. Ferguson,et al.  Epithelial-mesenchymal interactions are required for msx 1 and msx 2 gene expression in the developing murine molar tooth. , 1993, Development.

[40]  P. Schnegelsberg,et al.  Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. , 1992, The Journal of biological chemistry.

[41]  J. Wozney,et al.  Effects of dentin proteins, transforming growth factor beta 1 (TGF beta 1) and bone morphogenetic protein 2 (BMP2) on the differentiation of odontoblast in vitro. , 1992, The International journal of developmental biology.

[42]  M. Bienz.  Molecular mechanisms of determination in Drosophila. , 1992, Current opinion in cell biology.

[43]  N. Copeland,et al.  The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGFβ superfamily , 1992, Cell.

[44]  H. Oppermann,et al.  Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. , 1992, The Journal of biological chemistry.

[45]  J. Wozney,et al.  The bone morphogenetic protein family and osteogenesis , 1992, Molecular reproduction and development.

[46]  T. Moehl,et al.  Primate dentine extracellular matrix induces bone differentiation in heterotopic sites of the baboon (Papio ursinus). , 1992, Journal of periodontal research.

[47]  J. Gurdon.  The generation of diversity and pattern in animal development , 1992, Cell.

[48]  B. Hogan,et al.  The DVR gene family in embryonic development. , 1991, Trends in genetics : TIG.

[49]  A. Vaahtokari,et al.  Expression of syndecan gene is induced early, is transient, and correlates with changes in mesenchymal cell proliferation during tooth organogenesis. , 1991, Developmental biology.

[50]  A. Reddi,et al.  Osteogenin (bone morphogenetic protein-3) stimulates cartilage formation by chick limb bud cells in vitro. , 1991, Developmental biology.

[51]  N. Cunningham,et al.  Recent progress in bone induction by osteogenin and bone morphogenetic proteins: challenges for biomechanical and tissue engineering. , 1991, Journal of biomechanical engineering.

[52]  V. Rosen,et al.  Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[53]  H. Lesot,et al.  Preliminary studies on the in vivo morphogenetic properties of dentine matrix proteins. , 1990, Biomaterials.

[54]  E. Drier,et al.  OP‐1 cDNA encodes an osteogenic protein in the TGF‐beta family. , 1990, The EMBO journal.

[55]  V. Rosen,et al.  Recombinant human bone morphogenetic protein induces bone formation. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[56]  B. Hogan,et al.  Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. , 1989, Genes & development.

[57]  E. Chen,et al.  Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor beta gene superfamily. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[58]  V. Rosen,et al.  Novel regulators of bone formation: molecular clones and activities. , 1988, Science.

[59]  A. Lumsden.  Spatial organization of the epithelium and the role of neural crest cells in the initiation of the mammalian tooth germ. , 1988, Development.

[60]  I. Thesleff,et al.  Tissue interactions in tooth development. , 1981, Differentiation; research in biological diversity.

[61]  M. Urist,et al.  Bone: Formation by Autoinduction , 1965, Science.

[62]  P. M. Butler.  THE ONTOGENY OF MOLAR PATTERN , 1956 .

[63]  S. Keränen,et al.  The enamel knot as a signaling center in the developing mouse tooth , 1996, Mechanisms of Development.

[64]  V. Rosen,et al.  Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. , 1996, Growth factors.

[65]  A. Vaahtokari,et al.  Epithelial-mesenchymal signaling during tooth development. , 1995, Connective tissue research.

[66]  N. Copeland,et al.  Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3. , 1995, Growth factors.

[67]  H. Lesot,et al.  Odontoblast differentiation. , 1995, The International journal of developmental biology.

[68]  D. Kingsley,et al.  What do BMPs do in mammals? Clues from the mouse short-ear mutation. , 1994, Trends in genetics : TIG.

[69]  C. Tickle,et al.  Bone morphogenetic proteins and a signalling pathway that controls patterning in the developing chick limb. , 1994, Development.

[70]  E. Kollar,et al.  The induction of odontogenesis in non-dental mesenchyme combined with early murine mandibular arch epithelium. , 1987, Archives of oral biology.