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Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations.
Gray RS, Wilm TP, Smith J, Bagnat M, Dale RM, Topczewski J, Johnson SL, Solnica-Krezel L
(2014) Dev Biol 386: 72-85
MeSH Terms: Alleles, Animals, Collagen Type VIII, Crosses, Genetic, Gene Expression Regulation, Developmental, In Situ Hybridization, Meiosis, Microscopy, Confocal, Microscopy, Electron, Transmission, Mutation, Notochord, Osteoblasts, Protein-Lysine 6-Oxidase, Spine, Time Factors, Zebrafish
Show Abstract · Added March 20, 2014
Congenital vertebral malformations (CVM) occur in 1 in 1000 live births and in many cases can cause spinal deformities, such as scoliosis, and result in disability and distress of affected individuals. Many severe forms of the disease, such as spondylocostal dystostosis, are recessive monogenic traits affecting somitogenesis, however the etiologies of the majority of CVM cases remain undetermined. Here we demonstrate that morphological defects of the notochord in zebrafish can generate congenital-type spine defects. We characterize three recessive zebrafish leviathan/col8a1a mutant alleles ((m531, vu41, vu105)) that disrupt collagen type VIII alpha1a (col8a1a), and cause folding of the embryonic notochord and consequently adult vertebral column malformations. Furthermore, we provide evidence that a transient loss of col8a1a function or inhibition of Lysyl oxidases with drugs during embryogenesis was sufficient to generate vertebral fusions and scoliosis in the adult spine. Using periodic imaging of individual zebrafish, we correlate focal notochord defects of the embryo with vertebral malformations (VM) in the adult. Finally, we show that bends and kinks in the notochord can lead to aberrant apposition of osteoblasts normally confined to well-segmented areas of the developing vertebral bodies. Our results afford a novel mechanism for the formation of VM, independent of defects of somitogenesis, resulting from aberrant bone deposition at regions of misshapen notochord tissue.
Copyright © 2013 Elsevier Inc. All rights reserved.
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1 Members
0 Resources
16 MeSH Terms
Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas.
Pickup MW, Laklai H, Acerbi I, Owens P, Gorska AE, Chytil A, Aakre M, Weaver VM, Moses HL
(2013) Cancer Res 73: 5336-46
MeSH Terms: Animals, Carcinogenesis, Collagen, Enzyme Inhibitors, Female, Fibroblasts, Focal Adhesion Kinase 1, Humans, In Situ Hybridization, Keratin-14, Lung Neoplasms, Mammary Neoplasms, Experimental, Mice, Mice, Transgenic, Microscopy, Atomic Force, Myeloid Cells, Phosphorylation, Protein-Lysine 6-Oxidase, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Stromal Cells, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
The tumor stromal environment can dictate many aspects of tumor progression. A complete understanding of factors driving stromal activation and their role in tumor metastasis is critical to furthering research with the goal of therapeutic intervention. Polyoma middle T-induced mammary carcinomas lacking the type II TGF-β receptor (PyMT(mgko)) are highly metastatic compared with control PyMT-induced carcinomas (PyMT(fl/fl)). We hypothesized that the PyMT(mgko)-activated stroma interacts with carcinoma cells to promote invasion and metastasis. We show that the extracellular matrix associated with PyMT(mgko) tumors is stiffer and has more fibrillar collagen and increased expression of the collagen crosslinking enzyme lysyl oxidase (LOX) compared with PyMT(fl/fl) mammary carcinomas. Inhibition of LOX activity in PyMT(mgko) mice had no effect on tumor latency and size, but significantly decreased tumor metastasis through inhibition of tumor cell intravasation. This phenotype was associated with a decrease in keratin 14-positive myoepithelial cells in PyMT(mgko) tumors following LOX inhibition as well as a decrease in focal adhesion formation. Interestingly, the primary source of LOX was found to be activated fibroblasts. LOX expression in these fibroblasts can be driven by myeloid cell-derived TGF-β, which is significantly linked to human breast cancer. Overall, stromal expansion in PyMT(mgko) tumors is likely caused through the modulation of immune cell infiltrates to promote fibroblast activation. This feeds back to the epithelium to promote metastasis by modulating phenotypic characteristics of basal cells. Our data indicate that epithelial induction of microenvironmental changes can play a significant role in tumorigenesis and attenuating these changes can inhibit metastasis. Cancer Res; 73(17); 5336-46. ©2013 AACR.
1 Communities
2 Members
0 Resources
24 MeSH Terms
Pancreas-specific Cre driver lines and considerations for their prudent use.
Magnuson MA, Osipovich AB
(2013) Cell Metab 18: 9-20
MeSH Terms: Animals, DNA Nucleotidyltransferases, Extracellular Matrix Proteins, Integrases, Mice, Mice, Knockout, Mice, Transgenic, Models, Animal, Pancreas, Pancreatic Hormones, Protein-Lysine 6-Oxidase, Rats, Rats, Transgenic, Recombination, Genetic, Transgenes
Show Abstract · Added August 1, 2013
Cre/LoxP has broad utility for studying the function, development, and oncogenic transformation of pancreatic cells in mice. Here we provide an overview of the Cre driver lines that are available for such studies. We discuss how variegated expression, transgene silencing, and recombination in undesired cell types have conspired to limit the performance of these lines, sometimes leading to serious experimental concerns. We also discuss preferred strategies for achieving high-fidelity driver lines and remind investigators of the continuing need for caution when interpreting results obtained from any Cre/LoxP-based experiment performed in mice.
Copyright © 2013 Elsevier Inc. All rights reserved.
2 Communities
2 Members
0 Resources
15 MeSH Terms
Pet-1 is required across different stages of life to regulate serotonergic function.
Liu C, Maejima T, Wyler SC, Casadesus G, Herlitze S, Deneris ES
(2010) Nat Neurosci 13: 1190-8
MeSH Terms: 8-Hydroxy-2-(di-n-propylamino)tetralin, Age Factors, Analysis of Variance, Animals, Animals, Newborn, Cell Differentiation, Chromatin Immunoprecipitation, Estrogen Antagonists, Excitatory Amino Acid Antagonists, Extracellular Matrix Proteins, Gene Expression Regulation, Developmental, In Vitro Techniques, Luminescent Proteins, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Patch-Clamp Techniques, Protein-Lysine 6-Oxidase, RNA, Messenger, Raphe Nuclei, Receptor, Serotonin, 5-HT1A, Receptor, Serotonin, 5-HT1B, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Receptor Agonists, Somatosensory Cortex, Tamoxifen, Transcription Factors, Tryptophan Hydroxylase, Xanthenes
Show Abstract · Added April 22, 2013
Transcriptional cascades are required for the specification of serotonin (5-HT) neurons and behaviors modulated by 5-HT. Several cascade factors are expressed throughout the lifespan, which suggests that their control of behavior might not be temporally restricted to programming normal numbers of 5-HT neurons. We used new mouse conditional targeting approaches to investigate the ongoing requirements for Pet-1 (also called Fev), a cascade factor that is required for the initiation of 5-HT synthesis, but whose expression persists into adulthood. We found that Pet-1 was required after the generation of 5-HT neurons for multiple steps in 5-HT neuron maturation, including axonal innervation of the somatosensory cortex, expression of appropriate firing properties, and the expression of the Htr1a and Htr1b autoreceptors. Pet-1 was still required in adult 5-HT neurons to preserve normal anxiety-related behaviors through direct autoregulated control of serotonergic gene expression. These findings indicate that Pet-1 is required across the lifespan of the mouse and that behavioral pathogenesis can result from both developmental and adult-onset alterations in serotonergic transcription.
0 Communities
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1 Resources
34 MeSH Terms
Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition.
Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH
(2007) J Clin Invest 117: 3810-20
MeSH Terms: Animals, Calcium-Binding Proteins, Cell Hypoxia, Cell Movement, Chronic Disease, Collagen, Epithelial Cells, Extracellular Matrix, Fibrosis, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Tubules, Proximal, Mice, Mice, Knockout, Protein-Lysine 6-Oxidase, S100 Calcium-Binding Protein A4, S100 Proteins, Signal Transduction, Up-Regulation, Ureteral Obstruction
Show Abstract · Added September 9, 2013
Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.
0 Communities
1 Members
1 Resources
20 MeSH Terms