Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Msx2, a member of the highly conserved and widely distributed msh homeobox gene family, is expressed in a variety of sites in the vertebrate embryo, including craniofacial structures, heart, limb buds and otic and optic vesicles. In many of these sites, its expression is regulated by tissue interactions. Here we address the cis-trans regulatory interactions that direct Msx2 expression to specific regions of the embryo and enable it to respond to tissue interactions. We created a series of Msx2-lacZ fusion constructs with varying amounts of Msx2 genomic sequences. These were introduced into mouse embryos and their expression monitored by staining for beta-galactosidase activity. A construct bearing 5.2 kb of 5' flanking sequence, the intron, both exons and 3 kb of 3' flanking sequence was expressed in a pattern that closely resembled that of the endogenous Msx2 gene. In the E12.5 embryo, sites of expression included craniofacial mesenchyme, portions of the neural ectoderm, mesoderm in the distal limb bud and the overlying apical ectodermal ridge (AER). Removal of intronic and 3' UTR sequences slightly altered the pattern of Msx2 expression in the neural ectoderm of the E12 embryo. Deletion of 5' flanking sequences to -0.5 kb eliminated Msx2 expression in all sites except the AER. The proximal Msx2 promoter, including sequences required for the AER-specific expression of the -0.5 lacZ transgene, is highly conserved between mouse and human, one stretch exhibiting 100% identity over 72 bp. This conservation suggests that the AER element is under remarkably tight evolutionary constraint.
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PMID:Regulation of the Msx2 homeobox gene during mouse embryogenesis: a transgene with 439 bp of 5' flanking sequence is expressed exclusively in the apical ectodermal ridge of the developing limb. 789 2

We have generated a null allele of the mouse Msx1 homeobox gene by insertion of an nlacZ reporter gene into its homeobox. The sensitivity of beta-galactosidase detection permitted us to reveal novel aspects of Msx1 gene expression in heterozygous embryos, in particular in ectoderm and mesoderm during gastrulation, and in migrating neural crest cells. Homozygous mutant mice die at birth with facial defects (see Satokata, I. and Maas, R. (1994) Msx1 deficient mice exhibit cleft palate and abnormalities of craniofacial and tooth development. Nat. Genet. 6, 348-356). To investigate the reason for this limited phenotype, we compared the pattern of Msx1 expression with that of the closely related Msx2 gene in wild type embryos and in Msx1-/- mutants. Notably, whereas the expression of Msx1 and Msx2 overlap in the developing limb, this is not the case in the facial regions most affected in the mutant.
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PMID:Insertional mutation of the mouse Msx1 homeobox gene by an nlacZ reporter gene. 925 50

Msx and Dlx homeobox genes encode for transcription factors that control early morphogenesis. More specifically, Msx-1, Msx-2, and Dlx-2 homeobox genes contribute to the initial patterning of the dentition. The present study is devoted to the potential role of those homeobox genes during the late formation of mineralized tissues, using the rodent incisor as an experimental system. The continuously erupting mandibular incisor allows (1) the coinvestigation of the whole sequences of amelogenesis and dentinogenesis, aligned along the main dental axis in a single sample in situ and (2) the differential characterization of transcripts generated by epithelial and ectomesenchymal odontogenic cells. Northern blot experiments on microdissected cells showed the continuing expression of Msx-2 and Dlx-2 in the later stages of dental biomineralization, differentially in epithelial and ectomesenchymal compartments. Transgenic mice produced with LacZ reporter constructs for Dlx-2 and Msx-1 were used to detect different components of the gene expression patterns with the sensitive beta-galactosidase histoenzymology. The results show a prominent epithelial involvement of Dlx-2, with stage-specific variations in the cells involved in enamel formation. Quantitative analyses identified specific modulations of Dlx-2 expression in ameloblasts depending on the anatomical sites of the incisor, showing more specifically an inverse linear relationship between the Dlx-2 promoter activity level and enamel thickness. This investigation extends the role of homeoproteins to postmitotic stages, which would control secretory cell activity, in a site-specific manner as shown here for Dlx-2.
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PMID:Biomineralization, life-time of odontogenic cells and differential expression of the two homeobox genes MSX-1 and DLX-2 in transgenic mice. 1075 May 57

The nuclear matrix protein Msx2-interacting nuclear target protein (MINT) is a transcription factor that regulates the expression of key transcriptional effectors in diverse signaling pathways. To further understand the function and mechanism of the MINT-mediated transcription regulation, the yeast two-hybrid system was employed to screen proteins that interact with the C-terminal fragment of MINT. From a cDNA library of human lymph nodes, a cDNA encoding the ubiquitin-conjugating enzyme UbcH8 was identified. Using different truncated versions of MINT, we show that the C-terminal Spen paralog and ortholog C-terminal domain (SPOC) domain, which has been demonstrated to mediate interactions between MINT and a panel of other molecules, might be responsible for interaction between MINT and UbcH8 in yeast, as confirmed by the beta-galactosidase assay. The interaction between MINT and UbcH8 in mammalian cells was further proved by a series of biochemical assays including the mammalian two-hybrid assay, GST pull-down assay, and co-immunoprecipitation assay. Using a reporter system, we found that MINT-mediated transcription suppression was sensitive to MG132, an inhibitor of the proteosome system. These results suggest a novel mechanism of MINT-mediated transcription regulation, and might be helpful for understanding functions of MINT.
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PMID:The Spen homolog Msx2-interacting nuclear target protein interacts with the E2 ubiquitin-conjugating enzyme UbcH8. 1658 36

The physiological function of the transcription factor Msx2 in tooth and alveolar bone was analysed using a knock-in transgenic mouse line. In this mouse line, the beta-galactosidase gene was used to disrupt Msx2: thus, beta-galactosidase expression was driven by the Msx2 promoter, but Msx2 was not produced. This allowed to monitor Msx2 expression using a beta-galactosidase assay. Msx2 transgenic mice ubiquitously and continuously expressed the mutated Msx2-nlacZ gene in cells of the complex formed by tooth and alveolar bone. Msx2 -/- homozygous mice displayed a wide spectrum of alterations in tooth eruption and morphology as well as dental and periodontal defects from the first post-natal weeks up to 6 months. These defects culminated with the formation of an odontogenic tumour at the mandibular third molar site. This study suggests that bone resorption is a functional target of Msx2 in the alveolar compartment, since Msx2 was expressed in osteoclasts, with the highest expression levels found in the active sites of bone modelling associated with tooth eruption and root elongation. The RANK osteoclast differentiation pathway was affected in microdissected Msx2 -/- mouse alveolar bone (as inferred by RANK ligand mRNA levels) compared to basal bone and wild-type controls. Decreased alveolar osteoclast activity was observed in Msx2 -/- mice, similar to that seen in osteopetrosis, another condition in which osteoclast activity is impaired and odontogenic tumours form. These data suggest a pleiotropic role for Msx2 in oral bone growth from birth until adult homeostasis. RANK pathway appeared to be modulated by Msx2, in addition to the previously reported modulations of BMP4 and laminin5alpha3 in early tooth development. Non-overlapping Msx1 and Msx2 expression patterns suggested that these two homeogenes play non-redundant roles in skeletal growth, with Msx1 targeting basal bone and Msx2 targeting alveolar bone. This study provides a detailed analysis of the phenotype resulting from the Msx2 null mutation and identifies the impact of Msx1 and Msx2 on post-natal oral bone growth.
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PMID:Msx2 -/- transgenic mice develop compound amelogenesis imperfecta, dentinogenesis imperfecta and periodental osteopetrosis. 1787 71

Arterial calcification is common in patients with type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and other chronic inflammatory disorders. Arterial calcification is associated with significant morbidity and increased early mortality. The molecular signature of vascular calcification in diabetes is strikingly similar to that of CKD. Low-grade arterial inflammation is common to both conditions, and increased levels of tumor necrosis factor-alpha (TNF-alpha) have been reported in both DM and CKD. Recently, we described a novel TNF-alpha regulated Msx2-Wnt osteogenic program that regulates arterial calcification in an animal model of type 2 DM. TNF-alpha induces the osteogenic bone morphogenetic protein-2 (BMP-2), Msx2, Wnt3a, and Wnt7a mRNAs and leads to increased aortic calcium accumulation. Treatment with the TNF-alpha neutralizing antibody infliximab abrogates aortic BMP-2-Msx2-Wnt3a and Wnt7a signaling and attenuates aortic calcium accumulation significantly. Mice with vascular TNF-alpha augmented by the SM22-TNF-alpha transgene upregulate the aortic Msx2-Wnt3a/Wnt7a axis. Furthermore, SM22-TNF-alphaTg;TOPGAL mice exhibit greater beta-galactosidase reporter staining versus TOPGAL siblings in the aorta and coronaries, which indicates enhanced mural Wnt signaling in response to TNF-alpha. Thus, inflammatory TNF-alpha signals promote aortic osteogenic Msx2-Wnt programs in type 2 DM, and arterial calcification in this model is a TNF-alpha-driven Wnt-opathy. Having established the role of TNF-alpha in diabetic vascular calcification, an unmet need exists to evaluate the role of TNF-alpha and Msx2-Wnt signals in CKD-related calcification models. If validated in these models, then these findings will have significant therapeutic applications.
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PMID:Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy. 1843 4

Msx2 is a homeodomain transcription factor first identified in craniofacial bone and human femoral osteoblasts. We hypothesized that Msx2 might activate skeletal Wnt signaling. Therefore, we analyzed the effects of CMV-Msx2 transgene (Msx2Tg) expression on skeletal physiology and composition. Skeletal Msx2 expression was increased 2-3-fold by Msx2Tg, with expanded protein accumulation in marrow, secondary ossification centers, and periosteum. Microcomputed tomography established increased bone volume in Msx2Tg mice, with increased numbers of plate-like trabeculae. Histomorphometry revealed increased bone formation in Msx2Tg mice versus non-Tg siblings, arising from increased osteoblast numbers. While decreasing adipogenesis, Msx2Tg increased osteogenic differentiation via mechanisms inhibited by Dkk1, an antagonist of Wnt receptors LRP5 and LRP6. Bone from Msx2Tg mice elaborated higher levels of Wnt7 canonical agonists, with diminished Dkk1, changes that augment canonical signaling. Analysis of non-Tg and Msx2Tg siblings possessing the TOPGAL reporter confirmed this; Msx2Tg up-regulated skeletal beta-galactosidase expression (p </= 0.01), along with Wnt7a and Wnt7b, and reduced circulating Dkk1. To better understand molecular mechanisms, we studied C3H10T1/2 osteoprogenitor cells. As in bone, Msx2 increased Wnt7 genes and down-regulated Dkk1, while inducing the osteoblast gene alkaline phosphatase. Msx2-directed RNA interference increased Dkk1 expression and promoter activity, while reducing Wnt7a, Wnt7b, and alkaline phosphatase. Moreover, Msx2 inhibited Dkk1 promoter activity and reduced RNA polymerase association with Dkk1 chromatin. RNA interference-mediated knockdown of Wnt7a, Wnt7b, and LRP6 significantly reduced Msx2-induced alkaline phosphatase. Msx2 exerts bone anabolism in part by reducing Dkk1 expression and enhancing Wnt signaling, thus promoting osteogenic differentiation of skeletal progenitors.
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PMID:Msx2 exerts bone anabolism via canonical Wnt signaling. 1848 99