Project description:Embryologically the tooth is derived from both the ectoderm and neural crest (ectomesenchyme). It is often used as a model to study how epithelialmesenchymal interactions can control differentiation and morphogenesis. During early development organs of ectodermal origin share both a set of signalling molecules and exhibit common morphological features, subsequently proceeding along separate developmental programs. Tooth development is a continuous process that can be divided into the initiation -, bud -, cap -, and bell-stages. In mice, tooth development begins at embryonic day 11.5 (E11.5), by thickening of the dental epithelium, while mineralization of enamel and dentin in first molar starts at postnatal day 0 (P0) (5). A multistep and complex process of the gene expression are involved in the early stage of tooth development. So far expression of more than 1300 genes and/or proteins have been detected during tooth germ development by microarrays/immunocytochemistry/in situ hybridization. Studies with mutant mice have identified a number of genes that regulate tooth development and morphology. For example, deficiency of Lef-1 or P63 arrests tooth development at early stages. Deficiency of Msx1 or Pax9 results in arrest of tooth development at the bud stage , while deficiency of Runx2/Cbfa1 or Sp3 inhibits cyto-differentiation of ameloblasts and/or odontoblasts. Shh is required for normal growth and morphogenesis, but is not essential for cyto-differentiation of the ameloblast and odontoblast populations. Ameloblastin and amelogenin knock-out mice develop severe enamel hypoplasia with abnormal ameloblast differentiation. Recently, new connections between retinoid metabolism and PPAR responses have been identified. It has also been shown that endogenous retinoic acid is necessary for the initiation of odontogenesis , and that some of the genes that catalyze the oxidation of retinaldehyde into retinoic acid, exhibit distinct patterns of expression in developing murine teeth. Little is known about functions of PPAR-a as regards tooth germs or mature teeth. It is, however, likely that mitochondrial oxidative metabolism well as fatty acid metabolism is enhanced in late odontogenesis. These are metabolic activities which in other tissues are stimulated by PPAR-a agonists. For this reason it was of interest to carry out comparative gene expression profiling of the first molar tooth germs of PPAR-a knock-out mouse and of the corresponding wild-type mice. The results suggest marked differences in gene expression, parts of which may be associated with an observed hypomineralization of enamel in the mature PPAR-a knock-out murine tooth.

Project description:The tooth is derived from both the ectoderm and the neural crest (ectomesenchyme). It is often used as a model for studies of the basic mechanisms of organ development, including differentiation, cellular interaction, morphogenesis, and mineralization of extracellular matrices. In mouse, tooth development begins at embryonic day 11.5 (E11.5) by thickening of the dental epithelium, whereas mineralization of enamel and dentin in first molars starts at postnatal day 0 (P0). Tooth development entails a multistep and complex process of gene expression. Studies with genetically modified mice have contributed substantially to our understanding of genes that regulate tooth development and morphology. MicroRNAs (miRNA) are a class of non-coding RNAs that regulate gene expression at a post-transcriptional level, and are considered as important regulatory molecules during foetal development. By binding to target mRNAs, miRNA induce mRNA decay or translation repression. Recent bioinformatic predictions of miRNA targets in vertebrates indicate that hundreds of miRNAs are responsible for regulation of expression of up to 30% of the human protein-coding genes. Recent experiments has verified that miRNAs can regulate expression of hundreds of mRNAs in cultured cells. Previous study has also shown that microarrays can be used to detect physiologically relevant effects of miRNAs on expression of mRNAs in vertebrates; miRNAs have been shown to alter expression of a greater number of transcripts than previously appreciated, primarily through interaction with 3M-4UTRs. Understanding the biological function of miRNAs require knowledge of their mRNA targets. Bioinformatic approaches have been used to predict mRNA targets, among which both transcription factors and pro-apoptopic genes were prominent candidates. The precise molecular function of miRNAs remains largely unknown and a better understanding may require loss-of-function studies in vivo. It has been shown that intravenous administration of a novel class of chemically engineered oligonucleotides termed M-^SantagomirsM-^T resulted in a marked reduction of corresponding miRNA levels in most tissues. This resulted in upregulated expression of hundreds of genes predicted to be repressed by miR-122 because these genes had a miR-122 recognition motif in their 3M-4UTR region. Paradoxically, antagomir treatment also revealed a significant number of downregulated genes that may be activated by miR-122. The mechanism by which miRNAs may activate gene expression in vivo is unknown. However, it may involve an indirect effect (the suppression of a transcriptional repressor), or alternatively, miRNA may have a direct effect on gene activation (e.g. chromatin remodeling). Studies of microRNA expression profiles of the developing murine molar tooth germ have shown these to be highly dynamic, some miRNAs being abundantly expressed during the early development of the molar tooth germ, while others are highly expressed only at later developmental stages. A recent study also suggested that miRNAs modulate tooth morphogenesis and ameloblast differentiation, perhaps largely by fine tuning conserved signaling networks. The function of microRNA-214 (miR-214) is unknown, however, it has been related to normal growth and skeletal development in mice. In tooth germs miR-214 is more highly expressed during later developmental stages. It was selected as a target for silencing using anti-miR-214. Here we report effects from injections of 1-100 pmol of anti-miR-214 close to developing first mandibular molar in newborn mice. At 24 hrs, or more, after injection significant changes in gene expression, and in levels of several correspondingly encoded proteins, were found in the tooth germ.

Dataset Information

Murine Tooth Embryoic Molar Germ; E11, 12, 16, 18

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