Genetically Engineered Mice: Tools To Understand Craniofacial Development

Ignelzi, Michael A.; Liu, Yi‐Hsin; Maxson, Robert E.; Snead, Malcolm L.

doi:10.1177/10454411950060030201

Cited by 22 publications

(13 citation statements)

References 105 publications

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“…Transgenic mice lines were prepared as described elsewhere (29,30). Briefly, fertilized eggs for microinjection were harvested from superovulated 6-week-old female F1(C57BL/6J F ϫ DBA/2JM) mice impregnated by inbred adult male (CBA/J) mice.…”

Section: Methodsmentioning

confidence: 99%

Dentin Sialoprotein and Dentin Phosphoprotein Overexpression during Amelogenesis

Paine

Luo

Wang

et al. 2005

Journal of Biological Chemistry

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The gene for dentin sialophosphoprotein produces a single protein that is post-translationally modified to generate two distinct extracellular proteins: dentin sialoprotein and dentin phosphoprotein. In teeth, dentin sialophosphoprotein is expressed primarily by odontoblast cells, but is also transiently expressed by presecretory ameloblasts. Because of this expression profile it appears that dentin sialophosphoprotein contributes to the early events of amelogenesis, and in particular to those events that result in the formation of the dentinoenamel junction and the adjacent "aprismatic" enamel. Using a transgenic animal approach we have extended dentin sialoprotein or dentin phosphoprotein expression throughout the developmental stages of amelogenesis. Overexpression of dentin sialoprotein results in an increased rate of enamel mineralization, however, the enamel morphology is not significantly altered. In wildtype animals, the inclusion of dentin sialoprotein in the forming aprismatic enamel may account for its increased hardness properties, when compared with bulk enamel. In contrast, the overexpression of dentin phosphoprotein creates "pitted" and "chalky" enamel of nonuniform thickness that is more prone to wear. Disruptions to the prismatic enamel structure are also a characteristic of the dentin phosphoprotein overexpressing animals. These data support the previous suggestion that dentin sialoprotein and dentin phosphoprotein have distinct functions related to tooth formation, and that the dentino-enamel junction should be viewed as a unique transition zone between enamel and the underlying dentin. These results support the notion that the dentin proteins expressed by presecretory ameloblasts contribute to the unique properties of the dentino-enamel junction.Dentin is an ectomesenchymal derived, collagen containing, calcified tissue that forms the major part of the tooth. Genetic diseases that result in abnormal dentin are classified in a subgrouping of dentinogenesis imperfecta. Dentinogenesis imperfecta type I (DI-I) 1 is always associated with one of the osteogenesis imperfectas, where mutations have been characterized in the following collagens: COL1A1, COL1A2, COL5A1, and COL2A1 (1), whereas dentinogenesis imperfecta type II (DI-II) is a disorder in dentin mineralization. Dentinogenesis imperfecta type III (DI-III) has a more extreme abnormal dental phenotype that impacts beyond dentin to the enamel and the pulps of affected teeth (2, 3).In dentin, two of the noncollagenous dentin matrix proteins are dentin siaolprotein (DSP) and dentin phosphoprotein (DPP). Both DSP and DPP are products of a single gene called dentin sialophosphoprotein (DSPP). Following transcription and translation of DSPP, the resulting product is post-translational cleaved to produce DSP and DPP that are primarily expressed in the dentin matrix (4). DPP (also known as phosphophoryn) is a highly acidic protein and is the major noncollagenous matrix component of dentin (ϳ90% of the dentin matrix is collagen) (5, 6). DSP is a glyco...

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Section: Methodsmentioning

confidence: 99%

Dentin Sialoprotein and Dentin Phosphoprotein Overexpression during Amelogenesis

Paine

Luo

Wang

et al. 2005

Journal of Biological Chemistry

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“…Animals-Dsp and Dpp transgenic mice were engineered as described previously (5,20,21). Breeding of the transgenic lines was not affected by the enamel phenotype.…”

Section: Methodsmentioning

confidence: 99%

Ectopic Expression of Dentin Sialoprotein during Amelogenesis Hardens Bulk Enamel

White

Paine

Ngan

et al. 2007

Journal of Biological Chemistry

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Dentin sialophosphpoprotein (Dspp) is transiently expressed in the early stage of secretory ameloblasts. The secretion of ameloblast-derived Dspp is short-lived, correlates to the establishment of the dentinoenamel junction (DEJ), and is consistent with Dspp having a role in producing the specialized firstformed harder enamel adjacent to the DEJ. Crack diffusion by branching and dissipation within this specialized first-formed enamel close to the DEJ prevents catastrophic interfacial damage and tooth failure. Once Dspp is secreted, it is subjected to proteolytic cleavage that results in two distinct proteins referred to as dentin sialoprotein (Dsp) and dentin phosphoprotein (Dpp). The purpose of this study was to investigate the biological and mechanical contribution of Dsp and Dpp to enamel formation. Transgenic mice were engineered to overexpress either Dsp or Dpp in their enamel organs. The mechanical properties (hardness and toughness) of the mature enamel of transgenic mice were compared with genetically matched and age-matched nontransgenic animals. Dsp and Dpp contributions to enamel formation greatly differed. The inclusion of Dsp in bulk enamel significantly and uniformly increased enamel hardness (20%), whereas the inclusion of Dpp weakened the bulk enamel. Thus, Dsp appears to make a unique contribution to the physical properties of the DEJ. Dsp transgenic animals have been engineered with superior enamel mechanical properties.Until recently, it was believed that ectoderm-derived ameloblasts and ectomesenchyme-derived odontoblasts only expressed matrix proteins that were exclusive to themselves. But it is now known that there is also a transient expression of dentin sialophosphpoprotein (Dspp) 2 in early ameloblasts, adjacent to the dentinoenamel junction (DEJ) (1-6). We propose that Dspp has a role in producing the specialized first-formed harder enamel adjacent to the DEJ. Such a localized spatio-temporal pattern of Dspp protein expression may contribute to remarkable crack-resistant properties of the DEJ.Specialized highly mineralized first-formed enamel, and specialized tubule-rich mantle dentin have long been known to be present close to the DEJ interface (7-9). Although there is an abrupt transition between dentin and enamel tissues at the DEJ interface (10 -13), it is now known that the DEJ area functions as a broad mechanical zone (14 -17). Crack diffusion by branching and dissipation within the specialized first-formed enamel close to the DEJ prevents catastrophic interfacial damage and tooth failure (18,19).We tested the prediction that overexpression of Dspp proteins throughout enamel formation would produce altered enamel material properties. In this study, we have examined the mechanical properties of enamel of transgenic mice that overexpress either Dsp or Dpp in ameloblasts within their enamel organs. EXPERIMENTAL PROCEDURESOur strategy was to ascertain the functions of selected known proteins acting during enamel biomineralization by overexpressing them in quantity and time so that a l...

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“…Inbred strains of mice (Thyagarajan et al, 2003), where individual variability is practically eliminated, have recently been explored in orthodontic studies Al-Qawasmi et al, 2006;Ignelzi et al, 1995;Oshiro et al, 2002). With the development of genetic engineering, it has become possible to analyze the effects of a single biological variable (encoded by a gene) in orthodontic responses.…”

Section: Introduction Orthodontic Tooth Movement Bone Response and Rmentioning

confidence: 99%

Orthodontic mechanotransduction and the role of the P2X7 receptor

Viecilli

Katona

Chen

et al. 2009

American Journal of Orthodontics and Dentofacial Orthopedics

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DEDICATIONTo my parents, who have supported my education. iv ACKNOWLEDGMENTSOne of the most important things I have learned during my PhD is the necessity of the existence of a working network of people that can help you achieve your goals. The more effectively this network functions, the higher the chance you will achieve the goals quickly.I would first like to thank my parents, who have unconditionally supported my decision to abandon a profitable private practice in Orthodontics, and return to humble student conditions while aiming for a full time academic career.I also thank my girlfriend Laura Kruter who has (almost always) been ok with my, some might say, not very sane ideas. Sometimes they do turn out fine, though (like this "PhD" one).I can hardly think of anyone else that could have complemented my work and ideas during this Program as well as Dr. Thomas Katona. While I was passionately conditioned to an idea, he was always rational and careful. While I was sometimes furious with a shortcoming, he was always temperate and humorous. When I ran into his office with some news about a project, he would always listen and almost never seem too busy to see me. While I was working and something went wrong, he would listen and wonder with me about the "whys" and "hows", instead of telling me what to do or express disappointment. He was even subject to some of my home culinary experiments. I was extremely fortunate to find someone that thought about science the same way I did, and that actually helped me with my project instead of just telling me what to do. I felt like we worked as a team, and that helped to increase my motivation during my studies. The third part of this project tested the role of the P2X7 receptor in the dentoalveolar morphology of C57B/6 mice. P2X7R KO (knockout) mice were compared to C57B/6 WT to identify differences in a maxillary molar and bone. Tooth dimensions viii were measured and 3D bone morphometry was conducted. No statistically significant differences were found between the two mouse types. P2X7R does not have a major effect on alveolar bone or tooth morphology.The final part examines the role of the P2X7 receptor in a controlled biomechanical model. Orthodontic mechanotransduction was compared in wild-type (WT) and P2X7R knock-out (KO) mice. Using Finite Element Analysis, mouse mechanics were scaled to produce typical human stress levels. Relationships between the biological responses and the calculated stresses were statistically tested and compared.There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in WT and KO. Orthodontic responses are related to the principal stress patterns in the PDL and the P2X7 receptor plays a significant role in their mechanotransduction.

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Genetically Engineered Mice: Tools To Understand Craniofacial Development

Cited by 22 publications

References 105 publications

Dentin Sialoprotein and Dentin Phosphoprotein Overexpression during Amelogenesis

Dentin Sialoprotein and Dentin Phosphoprotein Overexpression during Amelogenesis

Ectopic Expression of Dentin Sialoprotein during Amelogenesis Hardens Bulk Enamel

Orthodontic mechanotransduction and the role of the P2X7 receptor

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