The Experts below are selected from a list of 10404 Experts worldwide ranked by ideXlab platform
Richard L Maas - One of the best experts on this subject based on the ideXlab platform.
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Genetic interactions between Pax9 and MSX1 regulate lip development and several stages of tooth morphogenesis.
Developmental Biology, 2010Co-Authors: Mitsushiro Nakatomi, Richard L Maas, Yiping Chen, Ralf Kist, Xiu-ping Wang, Darren Key, Jennifer J. Lund, Annick Turbe-doan, Heiko PetersAbstract:Abstract Developmental abnormalities of craniofacial structures and teeth often occur sporadically and the underlying genetic defects are not well understood, in part due to unknown gene–gene interactions. Pax9 and MSX1 are co-expressed during craniofacial development, and mice that are single homozygous mutant for either gene exhibit cleft palate and an early arrest of tooth formation. Whereas in vitro assays have demonstrated that protein–protein interactions between Pax9 and MSX1 can occur, it is unclear if Pax9 and MSX1 interact genetically in vivo during development. To address this question, we compounded the Pax9 and MSX1 mutations and observed that double homozygous mutants exhibit an incompletely penetrant cleft lip phenotype. Moreover, in double heterozygous mutants, the lower incisors were consistently missing and we find that transgenic BMP4 expression partly rescues this phenotype. Reduced expression of Shh and Bmp2 indicates that a smaller “incisor field” forms in Pax9+/−;MSX1+/− mutants, and dental epithelial growth is substantially reduced after the bud to cap stage transition. This defect is preceded by drastically reduced mesenchymal expression of Fgf3 and Fgf10, two genes that encode known stimulators of epithelial growth during odontogenesis. Consistent with this result, cell proliferation is reduced in both the dental epithelium and mesenchyme of double heterozygous mutants. Furthermore, the developing incisors lack mesenchymal Notch1 expression at the bud stage and exhibit abnormal ameloblast differentiation on both labial and lingual surfaces. Thus, MSX1 and Pax9 interact synergistically throughout lower incisor development and affect multiple signaling pathways that influence incisor size and symmetry. The data also suggest that a combined reduction of PAX9 and MSX1 gene dosage in humans may increase the risk for orofacial clefting and oligodontia.
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Concerted action of MSX1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development.
Mechanisms of development, 2007Co-Authors: Jun Han, Mamoru Ishii, Pablo Bringas, Richard L Maas, Robert E Maxson, Yang ChaiAbstract:The homeobox genes MSX1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during embryonic development. Mutations in the MSX1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although MSX1 and Msx2 are both expressed throughout the entire development of the frontal bone, the frontal bone defect in MSX1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between MSX1 and Msx2 during early frontal bone development. To investigate this hypothesis, we generated MSX1(-/-);Msx2(-/-) mice. These double mutant embryos died at E17 to E18 with no formation of the frontal bone. There was no apparent defect in CNC migration into the presumptive frontal bone primordium, but differentiation of the frontal mesenchyme and establishment of the frontal primordium was defective, indicating that MSX1 and Msx2 genes are specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium. Mechanistically, our data suggest that Msx genes are critical for the expression of Runx2 in the frontonasal subpopulation of cranial neural crest cells and for differentiation of the osteogenic lineage. This early function of the Msx genes is likely independent of the Bmp signaling pathway.
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cranial neural crest derived mesenchymal proliferation is regulated by MSX1 mediated p19ink4d expression during odontogenesis
Developmental Biology, 2003Co-Authors: Jun Han, Richard L Maas, Henry M Sucov, Yoshihiro Ito, Jae Yong Yeo, Yang ChaiAbstract:Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in MSX1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of MSX1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in MSX1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of MSX1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene MSX1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of MSX1 may alternatively instruct the fate of these progenitor cells during craniofacial development.
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bmp4 rescues a non cell autonomous function of MSX1 in tooth development
Development, 2000Co-Authors: Marianna Bei, Klaus Kratochwil, Richard L MaasAbstract:The development of many organs depends on sequential epithelial-mesenchymal interactions, and the developing tooth germ provides a powerful model for elucidating the nature of these inductive tissue interactions. In MSX1-deficient mice, tooth development arrests at the bud stage when MSX1 is required for the expression of Bmp4 and Fgf3 in the dental mesenchyme (Bei, M. and Maas, R. (1998) Development 125, 4325–4333). To define the tissue requirements for MSX1 function, we performed tissue recombinations between wild-type and MSX1 mutant dental epithelium and mesenchyme. We show that through the E14.5 cap stage of tooth development, MSX1 is required in the dental mesenchyme for tooth formation. After the cap stage, however, tooth development becomes MSX1 independent, although our experiments identify a further late function of MSX1 in odontoblast and dental pulp survival. These results suggest that prior to the cap stage, the dental epithelium receives an MSX1-dependent signal from the dental mesenchyme that is necessary for tooth formation. To further test this hypothesis, MSX1 mutant tooth germs were first cultured with either BMP4 or with various FGFs for two days in vitro and then grown under the kidney capsule of syngeneic mice to permit completion of organogenesis and terminal differentiation. Previously, using an in vitro culture system, we showed that BMP4 stimulated the growth of MSX1 mutant dental epithelium (Chen, Y., Bei, M. Woo, I., Satokata, I. and Maas, R. (1996). Development 122, 3035–3044). Using the more powerful kidney capsule grafting procedure, we now show that when added to explanted MSX1-deficient tooth germs prior to grafting, BMP4 rescues MSX1 mutant tooth germs all the way to definitive stages of enamel and dentin formation. Collectively, these results establish a transient functional requirement for MSX1 in the dental mesenchyme that is almost fully supplied by BMP4 alone, and not by FGFs. In addition, they formally prove the postulated downstream relationship of BMP4 with respect to MSX1, establish the non-cell-autonomous nature of MSX1 during odontogenesis, and disclose an additional late survival function for MSX1 in odontoblasts and dental pulp.
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FGFs and BMP4 induce both MSX1-independent and MSX1-dependent signaling pathways in early tooth development
Development (Cambridge England), 1998Co-Authors: Marianna Bei, Richard L MaasAbstract:During early tooth development, multiple signaling molecules are expressed in the dental lamina epithelium and induce the dental mesenchyme. One signal, BMP4, has been shown to induce morphologic changes in dental mesenchyme and mesenchymal gene expression via MSX1, but BMP4 cannot substitute for all the inductive functions of the dental epithelium. To investigate the role of FGFs during early tooth development, we examined the expression of epithelial and mesenchymal Fgfs in wild-type and MSX1 mutant tooth germs and tested the ability of FGFs to induce Fgf3 and Bmp4 expression in wild-type and MSX1 mutant dental mesenchymal explants. Fgf8 expression is preserved in MSX1 mutant epithelium while that of Fgf3 is not detected in MSX1 mutant dental mesenchyme. Moreover, dental epithelium as well as beads soaked in FGF1, FGF2 or FGF8 induce Fgf3 expression in dental mesenchyme in an MSX1-dependent manner. These results indicate that, like BMP4, FGF8 constitutes an epithelial inductive signal capable of inducing the expression of downstream signaling molecules in dental mesenchyme via MSX1. However, the BMP4 and FGF8 signaling pathways are distinct. BMP4 cannot induce Fgf3 nor can FGFs induce Bmp4 expression in dental mesenchyme, even though both signaling molecules can induce MSX1 and MSX1 is necessary for Fgf3 and Bmp4 expression in dental mesenchyme. In addition, we have investigated the effects of FGFs and BMP4 on the distal-less homeobox genes Dlx1 and Dlx2 and we have clarified the relationship between Msx and Dlx gene function in the developing tooth. Dlx1,Dlx2 double
Yang Chai - One of the best experts on this subject based on the ideXlab platform.
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MSX1 and Dlx5 function synergistically to regulate frontal bone development.
genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi Iwata, Yang ChaiAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of MSX1 in mice results in multiple developmental defects including craniofacial malformations. Although Dlx5 is widely expressed during embryonic development, targeted null mutation of Dlx5 mainly affects the development of craniofacial bones. MSX1 and Dlx5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of MSX1/Dlx5 interaction in regulating frontal bone development, we generated MSX1 and Dlx5 double null mutant mice. In MSX1−/−;Dlx5−/− mice, the frontal bones defect was more severe than that of either MSX1−/− or Dlx5−/− mice. This aggravated frontal bone defect suggests that MSX1 and Dlx5 function synergistically to regulate osteogenesis. This synergistic effect of MSX1 and Dlx5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, Dlx5 requires MSX1 for its expression in the context of frontal bone development. Our study shows that MSX1/Dlx5 interaction is crucial for osteogenic induction during frontal bone development. genesis 48:645–655, 2010. © 2010 Wiley-Liss, Inc.
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MSX1 and dlx5 function synergistically to regulate frontal bone development
Genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi Iwata, Yang ChaiAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of MSX1 in mice results in multiple developmental defects including craniofacial malformations. Although Dlx5 is widely expressed during embryonic development, targeted null mutation of Dlx5 mainly affects the development of craniofacial bones. MSX1 and Dlx5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of MSX1/Dlx5 interaction in regulating frontal bone development, we generated MSX1 and Dlx5 double null mutant mice. In MSX1(-/-) ;Dlx5(-/-) mice, the frontal bones defect was more severe than that of either MSX1(-/-) or Dlx5(-/-) mice. This aggravated frontal bone defect suggests that MSX1 and Dlx5 function synergistically to regulate osteogenesis. This synergistic effect of MSX1 and Dlx5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, Dlx5 requires MSX1 for its expression in the context of frontal bone development. Our study shows that MSX1/Dlx5 interaction is crucial for osteogenic induction during frontal bone development.
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Concerted action of MSX1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development.
Mechanisms of development, 2007Co-Authors: Jun Han, Mamoru Ishii, Pablo Bringas, Richard L Maas, Robert E Maxson, Yang ChaiAbstract:The homeobox genes MSX1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during embryonic development. Mutations in the MSX1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although MSX1 and Msx2 are both expressed throughout the entire development of the frontal bone, the frontal bone defect in MSX1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between MSX1 and Msx2 during early frontal bone development. To investigate this hypothesis, we generated MSX1(-/-);Msx2(-/-) mice. These double mutant embryos died at E17 to E18 with no formation of the frontal bone. There was no apparent defect in CNC migration into the presumptive frontal bone primordium, but differentiation of the frontal mesenchyme and establishment of the frontal primordium was defective, indicating that MSX1 and Msx2 genes are specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium. Mechanistically, our data suggest that Msx genes are critical for the expression of Runx2 in the frontonasal subpopulation of cranial neural crest cells and for differentiation of the osteogenic lineage. This early function of the Msx genes is likely independent of the Bmp signaling pathway.
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cranial neural crest derived mesenchymal proliferation is regulated by MSX1 mediated p19ink4d expression during odontogenesis
Developmental Biology, 2003Co-Authors: Jun Han, Richard L Maas, Henry M Sucov, Yoshihiro Ito, Jae Yong Yeo, Yang ChaiAbstract:Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in MSX1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of MSX1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in MSX1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of MSX1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene MSX1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of MSX1 may alternatively instruct the fate of these progenitor cells during craniofacial development.
Yiping Chen - One of the best experts on this subject based on the ideXlab platform.
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Genetic interactions between Pax9 and MSX1 regulate lip development and several stages of tooth morphogenesis.
Developmental Biology, 2010Co-Authors: Mitsushiro Nakatomi, Richard L Maas, Yiping Chen, Ralf Kist, Xiu-ping Wang, Darren Key, Jennifer J. Lund, Annick Turbe-doan, Heiko PetersAbstract:Abstract Developmental abnormalities of craniofacial structures and teeth often occur sporadically and the underlying genetic defects are not well understood, in part due to unknown gene–gene interactions. Pax9 and MSX1 are co-expressed during craniofacial development, and mice that are single homozygous mutant for either gene exhibit cleft palate and an early arrest of tooth formation. Whereas in vitro assays have demonstrated that protein–protein interactions between Pax9 and MSX1 can occur, it is unclear if Pax9 and MSX1 interact genetically in vivo during development. To address this question, we compounded the Pax9 and MSX1 mutations and observed that double homozygous mutants exhibit an incompletely penetrant cleft lip phenotype. Moreover, in double heterozygous mutants, the lower incisors were consistently missing and we find that transgenic BMP4 expression partly rescues this phenotype. Reduced expression of Shh and Bmp2 indicates that a smaller “incisor field” forms in Pax9+/−;MSX1+/− mutants, and dental epithelial growth is substantially reduced after the bud to cap stage transition. This defect is preceded by drastically reduced mesenchymal expression of Fgf3 and Fgf10, two genes that encode known stimulators of epithelial growth during odontogenesis. Consistent with this result, cell proliferation is reduced in both the dental epithelium and mesenchyme of double heterozygous mutants. Furthermore, the developing incisors lack mesenchymal Notch1 expression at the bud stage and exhibit abnormal ameloblast differentiation on both labial and lingual surfaces. Thus, MSX1 and Pax9 interact synergistically throughout lower incisor development and affect multiple signaling pathways that influence incisor size and symmetry. The data also suggest that a combined reduction of PAX9 and MSX1 gene dosage in humans may increase the risk for orofacial clefting and oligodontia.
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rescue of cleft palate in MSX1 deficient mice by transgenic bmp4 reveals a network of bmp and shh signaling in the regulation of mammalian palatogenesis
Development, 2002Co-Authors: Zunyi Zhang, Xiang Zhao, Yiqiang Song, Xiaoyun Zhang, Cesar D Fermin, Yiping ChenAbstract:Cleft palate, the most frequent congenital craniofacial birth defects in humans, arises from genetic or environmental perturbations in the multi-step process of palate development. Mutations in the MSX1 homeobox gene are associated with non-syndromic cleft palate and tooth agenesis in humans. We have used MSX1 -deficient mice as a model system that exhibits severe craniofacial abnormalities, including cleft secondary palate and lack of teeth, to study the genetic regulation of mammalian palatogenesis. We found that MSX1 expression was restricted to the anterior of the first upper molar site in the palatal mesenchyme and that MSX1 was required for the expression of Bmp4 and Bmp2 in the mesenchyme and Shh in the medial edge epithelium (MEE) in the same region of developing palate. In vivo and in vitro analyses indicated that the cleft palate seen in MSX1 mutants resulted from a defect in cell proliferation in the anterior palatal mesenchyme rather than a failure in palatal fusion. Transgenic expression of human Bmp4 driven by the mouse MSX1 promoter in the MSX1 –/– palatal mesenchyme rescued the cleft palate phenotype and neonatal lethality. Associated with the rescue of the cleft palate was a restoration of Shh and Bmp2 expression, as well as a return of cell proliferation to the normal levels. Ectopic Bmp4 appears to bypass the requirement for MSX1 and functions upstream of Shh and Bmp2 to support palatal development. Further in vitro assays indicated that Shh (normally expressed in the MEE) activates Bmp2 expression in the palatal mesenchyme which in turn acts as a mitogen to stimulate cell division. MSX1 thus controls a genetic hierarchy involving BMP and Shh signals that regulates the growth of the anterior region of palate during mammalian palatogenesis. Our findings provide insights into the cellular and molecular etiology of the non-syndromic clefting associated with MSX1 mutations.
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transgenically ectopic expression of bmp4 to the MSX1 mutant dental mesenchyme restores downstream gene expression but represses shh and bmp2 in the enamel knot of wild type tooth germ
Mechanisms of Development, 2000Co-Authors: Xiang Zhao, Yanding Zhang, Zunyi Zhang, Yiqiang Song, Xiaoyun Zhang, Sigurd H Fromm, Yiping ChenAbstract:Bmp4 is a downstream gene of MSX1 in early mouse tooth development. In this study, we introduced the MSX1-Bmp4 transgenic allele to the MSX1 mutants in which tooth development is arrested at the bud stage in an effort of rescuing MSX1 mutant tooth phenotype in vivo. Ectopic expression of a Bmp4 transgene driven by the mouse MSX1promoter in the dental mesenchyme restored the expression of Lef-1 and Dlx2 but neither Fgf3 nor syndecan-1 in the MSX1 mutant molar tooth germ. The mutant phenotype of molar but not incisor could be partially rescued to progress to the cap stage. The MSX1-Bmp4 transgene was also able to rescue the alveolar processes and the neonatal lethality of the MSX1 mutants. In contrast, overexpression of Bmp4 in the wild type molar mesenchyme down-regulated Shh and Bmp2 expression in the enamel knot, the putative signaling center for tooth patterning, but did not produce a tooth phenotype. These results indicate that Bmp4 can bypass MSX1 function to partially rescue molar tooth development in vivo, and to support alveolar process formation. Expression of Shh and Bmp2 in the enamel knot may not represent critical signals for tooth patterning.
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MSX1 is required for the induction of patched by sonic hedgehog in the mammalian tooth germ
Developmental Dynamics, 1999Co-Authors: Yanding Zhang, Xiang Zhao, Tara R St Amand, Meifeng Zhang, Rajee Ramamurthy, Mengsheng Qiu, Yiping ChenAbstract:We have used the mouse developing tooth germ as a model system to explore the transmission of Sonic hedgehog (Shh) signal in the induction of Patched (Ptc). In the early developing molar tooth germ, Shh is expressed in the dental epithelium, and the transcripts of Shh downstream target genes Ptc and Gli1 are expressed in dental epithelium as well as adjacent mesenchymal tissue. The homeobox gene MSX1 is also expressed in the dental mesenchyme of the molar tooth germ at this time. We show here that the expression of Ptc, but not Gli1, was downregulated in the dental mesenchyme of MSX1 mutants. In wild-type E11.0 molar tooth mesenchyme SHH-soaked beads induced the expression of Ptc and Gli1. However, in MSX1 mutant dental mesenchyme SHH-soaked beads were able to induce Gli1 but failed to induce Ptc expression, indicating a requirement for MSX1 in the induction of Ptc by SHH. Moreover, we show that another signaling molecule, BMP4, was able to induce Ptc expression in wild-type dental mesenchyme, but induced a distinct expression pattern of Ptc in the MSX1 mutant molar mesenchyme. We conclude that in the context of the tooth germ MSX1 is a component of the Shh signaling pathway that leads to Ptc induction. Our results also suggest that the precise pattern of Ptc expression in the prospective tooth-forming region is controlled and coordinated by at least two inductive signaling pathways. Dev Dyn 1999;215:45–53. © 1999 Wiley-Liss, Inc.
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MSX1 controls inductive signaling in mammalian tooth morphogenesis
Development, 1996Co-Authors: Yiping Chen, Marianna Bei, Ichiro Satokata, Ian Woo, Richard L MaasAbstract:Members of the Msx homeobox family are thought to play important roles in inductive tissue interactions during vertebrate organogenesis, but their precise developmental function has been unclear. Mice deficient for MSX1 exhibit defects in craniofacial development and a failure of tooth morphogenesis, with an arrest in molar tooth development at the E13.5 bud stage. Because of its potential for experimental manipulation, the murine molar tooth germ provides a powerful system for studying the role of Msx genes in inductive signaling during organogenesis. To further analyze the role of MSX1 in regulating epithelial-mesenchymal interactions during tooth morphogenesis, we have examined the expression of several potential MSX1 downstream genes in MSX1 mutant tooth germs and we have performed functional experiments designed to order these genes into a pathway. Our results show that expression of Bone Morphogenetic Protein 4 (BMP4), the HMG box gene Lef1 and the heparan sulfate proteoglycan syndecan-1 is specifically reduced in MSX1 mutant dental mesenchyme, while expression of the extracellular matrix protein tenascin is unaffected. BMP4 soaked beads can induce Bmp4 and Lef1 expression in explanted wild-type dental mesenchymes, but only Lef1 expression in MSX1 mutant dental mesenchyme. We thus conclude that epithelial BMP4 induces its own expression in dental mesenchyme in a manner that requires MSX1. In turn, we show that addition of BMP4 to MSX1 deficient tooth germs bypasses the requirement for MSX1 and rescues epithelial development from the bud stage to the E14.5 cap stage. Lastly, we show that FGFs induce syndecan-1 expression in dental mesenchyme in a manner that also requires Msx-1. These results integrate MSX1 into a regulatory hierarchy in early tooth morphogenesis and demonstrate that MSX1 is not only expressed in dental mesenchyme in response to epithelial signals, but also in turn regulates the reciprocal expression of inductive signals in the mesenchyme which then act back upon the dental epithelium. We propose that Msx genes function repetitively during vertebrate organogenesis to permit inductive signaling to occur back and forth between tissue layers.
Benoît Robert - One of the best experts on this subject based on the ideXlab platform.
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MSX1 role in craniofacial bone morphogenesis
Bone, 2014Co-Authors: Ali Nassif, Dominique Hotton, Benoît Robert, Ariane Berdal, Fleur Meary, Ibtisam Senussi, Sophia Loiodice, Morad Bensidhoum, Sylvie BabajkoAbstract:Abstract The homeobox gene MSX1 encodes a transcription factor that is highly expressed during embryogenesis and postnatal development in bone. Mutations of the MSX1 gene in humans are associated with cleft palate and (or) tooth agenesis. A similar phenotype is observed in newborn mice invalidated for the MSX1 gene. However, little is known about MSX1 function in osteoblast differentiation and bone mineralization in vivo . In the present study, we aimed to explore the variations of individualized bone shape in a subtle way avoiding the often severe consequences associated with gene mutations. We established transgenic mice that specifically express MSX1 in mineral–matrix-secreting cells under the control of the mouse 2.3 kb collagen 1 alpha 1 (Col1α1) promoter, which enabled us to investigate MSX1 function in bone in vivo . Adult transgenic mice (MSX1-Tg) presented altered skull shape and mineralization resulting from increased MSX1 expression during bone development. Serial section analysis of the mandibles showed a high amount of bone matrix in these mice. In addition, osteoblast number, cell proliferation and apoptosis were higher in MSX1-Tg mice than in controls with regional differences that could account for alterations of bone shape. However, Von Kossa staining and μCT analysis showed that bone mineralization was lower in MSX1-Tg mice than in controls due to alteration of osteoblastic differentiation. MSX1 appears to act as a modeling factor for membranous bone; it stimulates trabecular bone metabolism but limits cortical bone growth by promoting apoptosis, and concomitantly controls the collagen-based mineralization process.
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MSX1 and Msx2 in limb mesenchyme modulate digit number and identity.
Developmental Dynamics, 2011Co-Authors: Vardina Bensoussan-trigano, Yvan Lallemand, Cécile Saint Cloment, Benoît RobertAbstract:MSX1 and Msx2 encode homeodomain transcription factors that play a crucial role in limb development. However, the limb phenotype of the double MSX1(null/null) Msx2(null/null) mutant is difficult to analyze, particularly along the anteroposterior axis, because of the complex effects of the double mutation on both ectoderm- and mesoderm-derived structures. Namely, in the mutant, formation of the apical ectodermal ridge (AER) is impaired anteriorly and, consequently, the subjacent mesenchyme does not form. Using the Cre/loxP system, we investigated the respective roles of Msx genes in ectoderm and mesoderm by generating conditional mutant embryos with no Msx activity solely in the mesoderm. In these mutants, the integrity of the ectoderm-derived AER was maintained, allowing formation of the anterior mesenchyme. With this strategy, we demonstrate that mesenchymal expression of MSX1 and Msx2 is required for proper Shh and Bmp4 signaling to specify digit number and identity.
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Analysis of MSX1; Msx2 double mutants reveals multiple roles for Msx genes in limb development
Development (Cambridge England), 2005Co-Authors: Yvan Lallemand, Casto Ramos, Antoine Bach, Marie-anne Nicola, Cécile Saint Cloment, Benoît RobertAbstract:The homeobox-containing genes MSX1 and Msx2 are highly expressed in the limb field from the earliest stages of limb formation and, subsequently, in both the apical ectodermal ridge and underlying mesenchyme. However, mice homozygous for a null mutation in either MSX1 or Msx2 do not display abnormalities in limb development. By contrast, MSX1; Msx2 double mutants exhibit a severe limb phenotype. Our analysis indicates that these genes play a role in crucial processes during limb morphogenesis along all three axes. Double mutant limbs are shorter and lack anterior skeletal elements (radius/tibia, thumb/hallux). Gene expression analysis confirms that there is no formation of regions with anterior identity. This correlates with the absence of dorsoventral boundary specification in the anterior ectoderm, which precludes apical ectodermal ridge formation anteriorly. As a result, anterior mesenchyme is not maintained, leading to oligodactyly. Paradoxically, polydactyly is also frequent and appears to be associated with extended Fgf activity in the apical ectodermal ridge, which is maintained up to 14.5 dpc. This results in a major outgrowth of the mesenchyme anteriorly, which nevertheless maintains a posterior identity, and leads to formation of extra digits. These defects are interpreted in the context of an impairment of Bmp signalling.
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MSX1 disruption leads to diencephalon defects and hydrocephalus
Developmental Dynamics, 2004Co-Authors: Casto Ramos, Benoît Robert, P Fernandezllebrez, Antoine Bach, Eduardo SorianoAbstract:such as those of the fimbria and the medulla. Timing analysis suggests that MSX1 nLacZ cells delaminate and migrate radially from these epithelia, mainly at embryonic days 14 –16, while immunohistochemistry studies reveal that some of the -galactosidase migrating cells are oligodendrocytes or astrocytes. Our results suggest that the MSX1 neuroepithelia of fimbria and medulla may be a source of glial precursors. The MSX1 mutants display severe hydrocephalus at birth, while the subcommissural organ, the habenula, and the posterior commissure fail to develop correctly. No label was detected in the mutant subcommissural organ using a specific antibody against Reissner’s fiber. Besides, the fasciculus retroflexus deviates close to the subcommissural organ, while the paraventricular thalamic nucleus shows histological disorganization. Our results implicate the MSX1 gene in the differentiation of the subcommissural organ cells and posterior commissure and that MSX1 protein may play a role in the pathfinding and bundling of the fasciculus retroflexus and in the structural arrangement of the paraventricular thalamic nucleus. Developmental Dynamics 230:446 – 460, 2004. © 2004 Wiley-Liss, Inc.
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MSX1 is required for dorsal diencephalon patterning
Development, 2003Co-Authors: Antoine Bach, Casto Ramos, Yvan Lallemand, Marie-anne Nicola, Luc Mathis, Mathilde Maufras, Benoît RobertAbstract:The dorsal midline of the neural tube has recently emerged as a major signaling center for dorsoventral patterning. Msx genes are expressed at the dorsal midline, although their function at this site remains unknown. Using MSX1 nlacZ mutant mice, we show that the normal expression domain of MSX1 is interrupted in the pretectum of mutant embryos. Morphological and gene expression data further indicate that a functional midline is not maintained along the whole prosomere 1 in MSX1 mutant mice. This results in the downregulation of genes expressed laterally to the midline in prosomere 1, confirming the importance of the midline as a signaling center. Wnt1 is essential for dorsoventral patterning of the neural tube. In the MSX1 mutant, Wnt1 is downregulated before the midline disappears, suggesting that its expression depends on MSX1 . Furthermore, electroporation in the chick embryo demonstrates that MSX1 can induce Wnt1 expression in the diencephalon neuroepithelium and in the lateral ectoderm. In double MSX1 / Msx2 mutants, Wnt1 expression is completely abolished at the dorsal midline of the diencephalon and rostral mesencephalon. This indicates that Msx genes may regulate Wnt1 expression at the dorsal midline of the neural tube. Based on these results, we propose a model in which Msx genes are intermediary between Bmp and Wnt at this site.
Jun Han - One of the best experts on this subject based on the ideXlab platform.
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MSX1 and Dlx5 function synergistically to regulate frontal bone development.
genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi Iwata, Yang ChaiAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of MSX1 in mice results in multiple developmental defects including craniofacial malformations. Although Dlx5 is widely expressed during embryonic development, targeted null mutation of Dlx5 mainly affects the development of craniofacial bones. MSX1 and Dlx5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of MSX1/Dlx5 interaction in regulating frontal bone development, we generated MSX1 and Dlx5 double null mutant mice. In MSX1−/−;Dlx5−/− mice, the frontal bones defect was more severe than that of either MSX1−/− or Dlx5−/− mice. This aggravated frontal bone defect suggests that MSX1 and Dlx5 function synergistically to regulate osteogenesis. This synergistic effect of MSX1 and Dlx5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, Dlx5 requires MSX1 for its expression in the context of frontal bone development. Our study shows that MSX1/Dlx5 interaction is crucial for osteogenic induction during frontal bone development. genesis 48:645–655, 2010. © 2010 Wiley-Liss, Inc.
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MSX1 and dlx5 function synergistically to regulate frontal bone development
Genesis, 2010Co-Authors: Il Hyuk Chung, Jun Han, Junichi Iwata, Yang ChaiAbstract:The Msx and Dlx families of homeobox proteins are important regulators for embryogenesis. Loss of MSX1 in mice results in multiple developmental defects including craniofacial malformations. Although Dlx5 is widely expressed during embryonic development, targeted null mutation of Dlx5 mainly affects the development of craniofacial bones. MSX1 and Dlx5 show overlapping expression patterns during frontal bone development. To investigate the functional significance of MSX1/Dlx5 interaction in regulating frontal bone development, we generated MSX1 and Dlx5 double null mutant mice. In MSX1(-/-) ;Dlx5(-/-) mice, the frontal bones defect was more severe than that of either MSX1(-/-) or Dlx5(-/-) mice. This aggravated frontal bone defect suggests that MSX1 and Dlx5 function synergistically to regulate osteogenesis. This synergistic effect of MSX1 and Dlx5 on the frontal bone represents a tissue specific mode of interaction of the Msx and Dlx genes. Furthermore, Dlx5 requires MSX1 for its expression in the context of frontal bone development. Our study shows that MSX1/Dlx5 interaction is crucial for osteogenic induction during frontal bone development.
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Concerted action of MSX1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development.
Mechanisms of development, 2007Co-Authors: Jun Han, Mamoru Ishii, Pablo Bringas, Richard L Maas, Robert E Maxson, Yang ChaiAbstract:The homeobox genes MSX1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during embryonic development. Mutations in the MSX1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although MSX1 and Msx2 are both expressed throughout the entire development of the frontal bone, the frontal bone defect in MSX1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between MSX1 and Msx2 during early frontal bone development. To investigate this hypothesis, we generated MSX1(-/-);Msx2(-/-) mice. These double mutant embryos died at E17 to E18 with no formation of the frontal bone. There was no apparent defect in CNC migration into the presumptive frontal bone primordium, but differentiation of the frontal mesenchyme and establishment of the frontal primordium was defective, indicating that MSX1 and Msx2 genes are specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium. Mechanistically, our data suggest that Msx genes are critical for the expression of Runx2 in the frontonasal subpopulation of cranial neural crest cells and for differentiation of the osteogenic lineage. This early function of the Msx genes is likely independent of the Bmp signaling pathway.
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cranial neural crest derived mesenchymal proliferation is regulated by MSX1 mediated p19ink4d expression during odontogenesis
Developmental Biology, 2003Co-Authors: Jun Han, Richard L Maas, Henry M Sucov, Yoshihiro Ito, Jae Yong Yeo, Yang ChaiAbstract:Neural crest cells are multipotential progenitors that contribute to various cell and tissue types during embryogenesis. Here, we have investigated the molecular and cellular mechanism by which the fate of neural crest cell is regulated during tooth development. Using a two- component genetic system for indelibly marking the progeny of neural crest cells, we provide in vivo evidence of a deficiency of CNC-derived dental mesenchyme in MSX1 null mutant mouse embryos. The deficiency of the CNC results from an elevated CDK inhibitor p19(INK4d) activity and the disruption of cell proliferation. Interestingly, in the absence of MSX1, the CNC-derived dental mesenchyme misdifferentiates and possesses properties consistent with a neuronal fate, possibly through a default mechanism. Attenuation of p19(INK4d) in MSX1 null mutant mandibular explants restores mitotic activity in the dental mesenchyme, demonstrating the functional significance of MSX1-mediated p19(INK4d) expression in regulating CNC cell proliferation during odontogenesis. Collectively, our results demonstrate that homeobox gene MSX1 regulates the fate of CNC cells by controlling the progression of the cell cycle. Genetic mutation of MSX1 may alternatively instruct the fate of these progenitor cells during craniofacial development.