28 results on '"Dekker JD"'
Search Results
2. Lymphoid origin of intrinsically activated plasmacytoid dendritic cells in mice.
- Author
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Araujo AM, Dekker JD, Garrison K, Su Z, Rhee C, Hu Z, Lee BK, Osorio D, Lee J, Iyer VR, Ehrlich LIR, Georgiou G, Ippolito G, Yi S, and Tucker HO
- Subjects
- Animals, Mice, Lymphocyte Activation, T-Lymphocytes immunology, T-Lymphocytes metabolism, Mice, Inbred C57BL, Gene Expression Profiling, Lymphoid Progenitor Cells metabolism, Lymphoid Progenitor Cells cytology, Cell Lineage, Dendritic Cells immunology, Dendritic Cells metabolism
- Abstract
We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a . These CLP-derived pDCs, which we refer to as 'B-pDCs', have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN-α secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid-derived pDCs, display elevated levels of the cell surface receptor tyrosine kinase AXL, mirroring human AXL
+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice., Competing Interests: AA, JD, KG, ZS, CR, ZH, BL, DO, JL, VI, LE, GG, GI, SY, HT No competing interests declared, (© 2024, Araujo, Dekker et al.)- Published
- 2024
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3. Foxp1 Regulates Neural Stem Cell Self-Renewal and Bias Toward Deep Layer Cortical Fates.
- Author
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Pearson CA, Moore DM, Tucker HO, Dekker JD, Hu H, Miquelajáuregui A, and Novitch BG
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- Animals, Cell Differentiation physiology, Cell Self Renewal physiology, Humans, Mice, Neural Stem Cells cytology, Forkhead Transcription Factors metabolism, Neural Stem Cells metabolism, Repressor Proteins metabolism
- Abstract
The laminar architecture of the mammalian neocortex depends on the orderly generation of distinct neuronal subtypes by apical radial glia (aRG) during embryogenesis. Here, we identify critical roles for the autism risk gene Foxp1 in maintaining aRG identity and gating the temporal competency for deep-layer neurogenesis. Early in development, aRG express high levels of Foxp1 mRNA and protein, which promote self-renewing cell divisions and deep-layer neuron production. Foxp1 levels subsequently decline during the transition to superficial-layer neurogenesis. Sustained Foxp1 expression impedes this transition, preserving a population of cells with aRG identity throughout development and extending the early neurogenic period into postnatal life. FOXP1 expression is further associated with the initial formation and expansion of basal RG (bRG) during human corticogenesis and can promote the formation of cells exhibiting characteristics of bRG when misexpressed in the mouse cortex. Together, these findings reveal broad functions for Foxp1 in cortical neurogenesis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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4. The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias.
- Author
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Brown MA, Edwards MA, Alshiraihi I, Geng H, Dekker JD, and Tucker HO
- Subjects
- Animals, Cell Line, Tumor, Hematopoietic Stem Cell Transplantation methods, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase physiology, Humans, Leukemia genetics, Lymphocytes metabolism, Lymphocytes physiology, Lysine metabolism, Male, Mice, Mice, Inbred C57BL, Mixed Function Oxygenases genetics, Mixed Function Oxygenases metabolism, Proto-Oncogene Mas, Histone-Lysine N-Methyltransferase metabolism, Leukemia metabolism
- Abstract
The five membered SET and MYND Domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and proliferation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated as an oncogene in leukemias deriving from flawed hematopoietic stem cell (HSC) differentiation. We show here that conditional SMYD2 loss disrupts hematopoiesis at and downstream of the HSC via both apoptotic loss and transcriptional deregulation of HSC proliferation and disruption of Wnt-β-Catenin signaling. Yet, previously documented SMYD2 cell cycle targets were unscathed. Turning our analysis to human leukemias, we observed that SMYD2 is highly expressed in CML, MLLr-B-ALL, AML, T-ALL, and B-ALL leukemias and its levels in B-ALL correlate with poor survival. SMYD2 knockdown results in apoptotic death and loss of anchorage-independent transformation of each of these hematopoietic leukemias. These data provide an underlying mechanism by which SMYD2 acts during normal hematopoiesis and as a proto-oncogene in leukemia.
- Published
- 2020
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5. Loss of the FOXP1 Transcription Factor Leads to Deregulation of B Lymphocyte Development and Function at Multiple Stages.
- Author
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Dekker JD, Baracho GV, Zhu Z, Ippolito GC, Schmitz RJ, Rickert RC, and Tucker HO
- Subjects
- Animals, Forkhead Transcription Factors genetics, Mice, Knockout, Repressor Proteins genetics, B-Lymphocytes physiology, Cell Differentiation, Forkhead Transcription Factors physiology, Repressor Proteins physiology
- Abstract
The FOXP1 transcription factor is expressed throughout B cell development until its extinction just prior to terminal differentiation. Foxp1 nulls die of cardiac defects at midgestation, but adult rescue via fetal liver transfer led to a strong pre-B cell block. To circumvent these limitations and to investigate FOXP1 function at later stages of B cell differentiation, we generated and analyzed floxed (F) Foxp1 alleles deleted at pro-B, transitional (T) 1, and mature B cell stages. Mb-1cre -mediated deletion of Foxp1
F/F confirmed its requirement for pro-B to pre-B transition. Cd21- and Cd19cre deletion led to significant reduction of germinal center formation and a second block in differentiation at the T2/marginal zone precursor stage. T-dependent and -independent immunization of FOXP1 mutants led to reduction of Ag-specific IgM, whereas responses of class-switched Abs were unimpaired. Yet, unexpectedly, plasmablast and plasma cell numbers were significantly increased by in vitro BCR stimulation of Foxp1F/F splenic follicular B cells but rapidly lost, as they were highly prone to apoptosis. RNA sequencing, gene set enrichment analysis, and chromatin immunoprecipitation sequencing analyses revealed strong enrichment for signatures related to downregulation of immune responses, apoptosis, and germinal center biology, including direct activation of Bcl6 and downregulation of Aicda/AID, the primary effector of somatic hypermutation, and class-switch recombination. These observations support a role for FOXP1 as a direct transcriptional regulator at key steps underlying B cell development in the mouse., (Copyright © 2019 The Authors.)- Published
- 2019
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6. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme.
- Author
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Triplett TA, Garrison KC, Marshall N, Donkor M, Blazeck J, Lamb C, Qerqez A, Dekker JD, Tanno Y, Lu WC, Karamitros CS, Ford K, Tan B, Zhang XM, McGovern K, Coma S, Kumada Y, Yamany MS, Sentandreu E, Fromm G, Tiziani S, Schreiber TH, Manfredi M, Ehrlich LIR, Stone E, and Georgiou G
- Subjects
- Animals, Cancer Vaccines therapeutic use, Cell Line, Tumor, Humans, Neoplasms enzymology, Neoplasms immunology, Neoplasms metabolism, Tumor Microenvironment, Adjuvants, Immunologic therapeutic use, Hydrolases therapeutic use, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Kynurenine metabolism, Neoplasms drug therapy
- Abstract
Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8
+ lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.- Published
- 2018
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7. Foxp2 regulates anatomical features that may be relevant for vocal behaviors and bipedal locomotion.
- Author
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Xu S, Liu P, Chen Y, Chen Y, Zhang W, Zhao H, Cao Y, Wang F, Jiang N, Lin S, Li B, Zhang Z, Wei Z, Fan Y, Jin Y, He L, Zhou R, Dekker JD, Tucker HO, Fisher SE, Yao Z, Liu Q, Xia X, and Guo X
- Subjects
- Animals, Hindlimb metabolism, Humans, Mice, Mice, Knockout, Bone Remodeling genetics, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Locomotion genetics, Mutation, Repressor Proteins genetics, Repressor Proteins metabolism, Skull metabolism, Vocalization, Animal
- Abstract
Fundamental human traits, such as language and bipedalism, are associated with a range of anatomical adaptations in craniofacial shaping and skeletal remodeling. However, it is unclear how such morphological features arose during hominin evolution. FOXP2 is a brain-expressed transcription factor implicated in a rare disorder involving speech apraxia and language impairments. Analysis of its evolutionary history suggests that this gene may have contributed to the emergence of proficient spoken language. In the present study, through analyses of skeleton-specific knockout mice, we identified roles of Foxp2 in skull shaping and bone remodeling. Selective ablation of Foxp2 in cartilage disrupted pup vocalizations in a similar way to that of global Foxp2 mutants, which may be due to pleiotropic effects on craniofacial morphogenesis. Our findings also indicate that Foxp2 helps to regulate strength and length of hind limbs and maintenance of joint cartilage and intervertebral discs, which are all anatomical features that are susceptible to adaptations for bipedal locomotion. In light of the known roles of Foxp2 in brain circuits that are important for motor skills and spoken language, we suggest that this gene may have been well placed to contribute to coevolution of neural and anatomical adaptations related to speech and bipedal locomotion., Competing Interests: The authors declare no conflict of interest.
- Published
- 2018
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8. Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination.
- Author
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Lee BS, Lee BK, Iyer VR, Sleckman BP, Shaffer AL 3rd, Ippolito GC, Tucker HO, and Dekker JD
- Abstract
Recombination activating gene 1 (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining [V(D)J] segment recombination, an essential process for antigen receptor expression and lymphocyte development. The BCL11A transcription factor is required for B cell and plasmacytoid dendritic cell (pDC) development, but its molecular function(s) in early B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds directly to the RAG1 promoter as well as directly to regulatory regions of transcription factors previously implicated in both B cell and pDC development to activate RAG1 and RAG2 gene transcription in pro- and pre-B cells. We employed BCL11A overexpression with recombination substrates to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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9. Retraction for Lee et al., "The BCL11A Transcription Factor Directly Activates RAG Gene Expression and V(D)J Recombination".
- Author
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Lee BS, Dekker JD, Lee BK, Iyer VR, Sleckman BP, Shaffer AL 3rd, Ippolito GC, and Tucker PW
- Published
- 2017
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10. FOXP1 controls mesenchymal stem cell commitment and senescence during skeletal aging.
- Author
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Li H, Liu P, Xu S, Li Y, Dekker JD, Li B, Fan Y, Zhang Z, Hong Y, Yang G, Tang T, Ren Y, Tucker HO, Yao Z, and Guo X
- Subjects
- Adipogenesis physiology, Animals, Bone Marrow Cells cytology, CCAAT-Enhancer-Binding Protein-beta genetics, CCAAT-Enhancer-Binding Protein-beta metabolism, CCAAT-Enhancer-Binding Protein-delta genetics, CCAAT-Enhancer-Binding Protein-delta metabolism, Cell Line, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Forkhead Transcription Factors genetics, Humans, Mesenchymal Stem Cells cytology, Mice, Mice, Knockout, Osteogenesis physiology, Repressor Proteins genetics, Bone Marrow Cells metabolism, Cellular Senescence physiology, Forkhead Transcription Factors metabolism, Mesenchymal Stem Cells metabolism, Repressor Proteins metabolism
- Abstract
A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.
- Published
- 2017
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11. Forkhead Box Protein P1 Is Dispensable for Retina but Essential for Lens Development.
- Author
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Suzuki-Kerr H, Baba Y, Tsuhako A, Koso H, Dekker JD, Tucker HO, Kuribayashi H, and Watanabe S
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- Animals, Cataract metabolism, Cell Proliferation, Disease Models, Animal, Electroretinography, Forkhead Transcription Factors biosynthesis, Immunohistochemistry, Lens, Crystalline cytology, Lens, Crystalline growth & development, Mice, Mice, Inbred C57BL, Mice, Knockout, Polymerase Chain Reaction, Repressor Proteins biosynthesis, Retina cytology, Retina growth & development, Cataract genetics, Forkhead Transcription Factors genetics, Gene Expression Regulation, Developmental, Lens, Crystalline metabolism, RNA genetics, Repressor Proteins genetics, Retina metabolism
- Abstract
Purpose: Forkhead box protein P1 (Foxp1) is a transcriptional repressor expressed in many tissues. We identified Foxp1 as a highly expressed gene in retinal progenitor cells and investigated its roles during eye development., Methods: Mouse eyes with Foxp1 gain- or loss-of-function were established in vitro and in vivo., Results: Foxp1 overexpression in retinal progenitor cells resulted in reduced rod and increased cone photoreceptors. However, retina-specific knockout of Foxp1 was not associated with retinal differentiation abnormalities. Foxp1 was highly expressed in the lens during early development, and continued to be expressed in epithelial and cortical fiber cells until adulthood. At birth, analyses of Foxp1 lens-specific knockout (Foxp1-L-CKO) mice showed no gross morphologic changes in germinal or central epithelial cell compared to the controls. However, the numbers of proliferating and apoptotic cells were significantly increased in Foxp1-L-CKO mice. In addition, clear Y-structures were not observed in either the posterior or anterior sutures of the Foxp1-L-CKO lenses. Mature lenses of Foxp1-L-CKO mice were small and opaque. The fiber cell structure in the core and the cortical fiber cell columns were disturbed in Foxp1-L-CKO mice at postnatal day 14, potentially accounting for the opacity. In addition, epithelial cells were not aligned into columns along the transition zone in Foxp1-L-CKO mice. Taken together, these results suggest that Foxp1 has a role during lens growth in epithelial and differentiating fiber cells., Conclusions: Loss of Foxp1 results in loss of suture and fiber cell alignment, which eventually causes lens opacity, suggesting that Foxp1 has a key role in establishing cortical lens architecture.
- Published
- 2017
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12. Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1.
- Author
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Dekker JD, Park D, Shaffer AL 3rd, Kohlhammer H, Deng W, Lee BK, Ippolito GC, Georgiou G, Iyer VR, Staudt LM, and Tucker HO
- Subjects
- Cell Differentiation, Cell Line, Tumor, Humans, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Transcription, Genetic, B-Lymphocytes immunology, Forkhead Transcription Factors physiology, Lymphoma, Large B-Cell, Diffuse immunology, Repressor Proteins physiology
- Abstract
High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB cell to the plasmablast--the transient B-cell stage targeted in ABC-DLBCL transformation--by antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB "master regulator," BCL6 (B-cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical subtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.
- Published
- 2016
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13. FoxP1 orchestration of ASD-relevant signaling pathways in the striatum.
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Araujo DJ, Anderson AG, Berto S, Runnels W, Harper M, Ammanuel S, Rieger MA, Huang HC, Rajkovich K, Loerwald KW, Dekker JD, Tucker HO, Dougherty JD, Gibson JR, and Konopka G
- Subjects
- Animals, Autism Spectrum Disorder genetics, Cells, Cultured, Disease Models, Animal, Forkhead Transcription Factors genetics, Gene Expression Regulation genetics, Haploinsufficiency, Hippocampus physiopathology, Humans, Mice, Mice, Inbred C57BL, Mutation, Neurons pathology, Repressor Proteins genetics, Verbal Behavior physiology, Autism Spectrum Disorder physiopathology, Corpus Striatum physiopathology, Forkhead Transcription Factors metabolism, Repressor Proteins metabolism, Signal Transduction genetics
- Abstract
Mutations in the transcription factor Forkhead box p1 (FOXP1) are causative for neurodevelopmental disorders such as autism. However, the function of FOXP1 within the brain remains largely uncharacterized. Here, we identify the gene expression program regulated by FoxP1 in both human neural cells and patient-relevant heterozygous Foxp1 mouse brains. We demonstrate a role for FoxP1 in the transcriptional regulation of autism-related pathways as well as genes involved in neuronal activity. We show that Foxp1 regulates the excitability of striatal medium spiny neurons and that reduction of Foxp1 correlates with defects in ultrasonic vocalizations. Finally, we demonstrate that FoxP1 has an evolutionarily conserved role in regulating pathways involved in striatal neuron identity through gene expression studies in human neural progenitors with altered FOXP1 levels. These data support an integral role for FoxP1 in regulating signaling pathways vulnerable in autism and the specific regulation of striatal pathways important for vocal communication., (© 2015 Araujo et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2015
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14. Spinal Locomotor Circuits Develop Using Hierarchical Rules Based on Motorneuron Position and Identity.
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Hinckley CA, Alaynick WA, Gallarda BW, Hayashi M, Hilde KL, Driscoll SP, Dekker JD, Tucker HO, Sharpee TO, and Pfaff SL
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- Action Potentials physiology, Animals, Animals, Newborn, Calcium metabolism, Central Pattern Generators cytology, Electromyography, Embryo, Mammalian, Homeodomain Proteins metabolism, In Vitro Techniques, Luminescent Proteins genetics, Luminescent Proteins metabolism, Mice, Mice, Transgenic, Periodicity, Statistics, Nonparametric, Transcription Factors metabolism, Central Pattern Generators physiology, Locomotion physiology, Motor Neurons physiology, Nerve Net physiology, Spinal Cord cytology
- Abstract
The coordination of multi-muscle movements originates in the circuitry that regulates the firing patterns of spinal motorneurons. Sensory neurons rely on the musculotopic organization of motorneurons to establish orderly connections, prompting us to examine whether the intraspinal circuitry that coordinates motor activity likewise uses cell position as an internal wiring reference. We generated a motorneuron-specific GCaMP6f mouse line and employed two-photon imaging to monitor the activity of lumbar motorneurons. We show that the central pattern generator neural network coordinately drives rhythmic columnar-specific motorneuron bursts at distinct phases of the locomotor cycle. Using multiple genetic strategies to perturb the subtype identity and orderly position of motorneurons, we found that neurons retained their rhythmic activity-but cell position was decoupled from the normal phasing pattern underlying flexion and extension. These findings suggest a hierarchical basis of motor circuit formation that relies on increasingly stringent matching of neuronal identity and position., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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15. Foxp1 Regulates the Proliferation of Hair Follicle Stem Cells in Response to Oxidative Stress during Hair Cycling.
- Author
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Zhao J, Li H, Zhou R, Ma G, Dekker JD, Tucker HO, Yao Z, and Guo X
- Subjects
- Active Transport, Cell Nucleus, Animals, Cell Line, Cell Nucleus metabolism, Cell Proliferation, Forkhead Transcription Factors deficiency, Forkhead Transcription Factors genetics, Male, Mice, Reactive Oxygen Species metabolism, Repressor Proteins deficiency, Repressor Proteins genetics, S Phase, Thioredoxins metabolism, Forkhead Transcription Factors metabolism, Hair Follicle cytology, Hair Follicle growth & development, Oxidative Stress, Repressor Proteins metabolism, Stem Cells cytology
- Abstract
Hair follicle stem cells (HFSCs) in the bugle circularly generate outer root sheath (ORS) through linear proliferation within limited cycles during anagen phases. However, the mechanisms controlling the pace of HFSC proliferation remain unclear. Here we revealed that Foxp1, a transcriptional factor, was dynamically relocated from the nucleus to the cytoplasm of HFSCs in phase transitions from anagen to catagen, coupled with the rise of oxidative stress. Mass spectrum analyses revealed that the S468 phosphorylation of Foxp1 protein was responsive to oxidative stress and affected its nucleocytoplasmic translocation. Foxp1 deficiency in hair follicles led to compromised ROS accrual and increased HFSC proliferation. And more, NAC treatment profoundly elongated the anagen duration and HFSC proliferation in Foxp1-deficient background. Molecularly, Foxp1 augmented ROS levels through suppression of Trx1-mediated reductive function, thereafter imposing the cell cycle arrest by modulating the activity of p19/p53 pathway. Our findings identify a novel role for Foxp1 in controlling HFSC proliferation with cellular dynamic location in response to oxidative stress during hair cycling.
- Published
- 2015
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16. Smyd1 facilitates heart development by antagonizing oxidative and ER stress responses.
- Author
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Rasmussen TL, Ma Y, Park CY, Harriss J, Pierce SA, Dekker JD, Valenzuela N, Srivastava D, Schwartz RJ, Stewart MD, and Tucker HO
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Cell Cycle Proteins chemistry, Cell Cycle Proteins metabolism, Cell Proliferation, Chlorocebus aethiops, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Embryo, Mammalian embryology, Gene Expression Regulation, Developmental, Gene Knockout Techniques, Humans, Methylation, Mice, Molecular Sequence Data, Muscle Proteins deficiency, Muscle Proteins genetics, Transcription Factors deficiency, Transcription Factors genetics, Transcription, Genetic, Up-Regulation, DNA-Binding Proteins metabolism, Endoplasmic Reticulum Stress, Heart growth & development, Muscle Proteins metabolism, Myocardium cytology, Myocardium metabolism, Oxidative Stress, Transcription Factors metabolism
- Abstract
Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense-a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality.
- Published
- 2015
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17. Foxp1/2/4 regulate endochondral ossification as a suppresser complex.
- Author
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Zhao H, Zhou W, Yao Z, Wan Y, Cao J, Zhang L, Zhao J, Li H, Zhou R, Li B, Wei G, Zhang Z, French CA, Dekker JD, Yang Y, Fisher SE, Tucker HO, and Guo X
- Subjects
- Animals, Bone and Bones metabolism, COS Cells, Calcification, Physiologic, Chlorocebus aethiops, Chondrocytes pathology, Chondrogenesis genetics, Core Binding Factor Alpha 1 Subunit metabolism, Extremities embryology, Forkhead Transcription Factors deficiency, Forkhead Transcription Factors genetics, Gene Deletion, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Hypertrophy, Integrases metabolism, Mice, Transgenic, Protein Binding, Repressor Proteins deficiency, Repressor Proteins genetics, Chondrocytes metabolism, Forkhead Transcription Factors metabolism, Osteogenesis, Repressor Proteins metabolism
- Abstract
Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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18. An integrated cell purification and genomics strategy reveals multiple regulators of pancreas development.
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Benitez CM, Qu K, Sugiyama T, Pauerstein PT, Liu Y, Tsai J, Gu X, Ghodasara A, Arda HE, Zhang J, Dekker JD, Tucker HO, Chang HY, and Kim SK
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Genomics methods, Insulin-Secreting Cells cytology, Insulin-Secreting Cells physiology, Mice, Mutant Strains, Mice, Transgenic, Models, Statistical, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Reproducibility of Results, SOX9 Transcription Factor genetics, Stem Cells cytology, Stem Cells physiology, Cell Separation methods, Gene Expression Regulation, Developmental, Pancreas cytology, Pancreas embryology, Pancreas growth & development
- Abstract
The regulatory logic underlying global transcriptional programs controlling development of visceral organs like the pancreas remains undiscovered. Here, we profiled gene expression in 12 purified populations of fetal and adult pancreatic epithelial cells representing crucial progenitor cell subsets, and their endocrine or exocrine progeny. Using probabilistic models to decode the general programs organizing gene expression, we identified co-expressed gene sets in cell subsets that revealed patterns and processes governing progenitor cell development, lineage specification, and endocrine cell maturation. Purification of Neurog3 mutant cells and module network analysis linked established regulators such as Neurog3 to unrecognized gene targets and roles in pancreas development. Iterative module network analysis nominated and prioritized transcriptional regulators, including diabetes risk genes. Functional validation of a subset of candidate regulators with corresponding mutant mice revealed that the transcription factors Etv1, Prdm16, Runx1t1 and Bcl11a are essential for pancreas development. Our integrated approach provides a unique framework for identifying regulatory genes and functional gene sets underlying pancreas development and associated diseases such as diabetes mellitus.
- Published
- 2014
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19. Dendritic cell fate is determined by BCL11A.
- Author
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Ippolito GC, Dekker JD, Wang YH, Lee BK, Shaffer AL 3rd, Lin J, Wall JK, Lee BS, Staudt LM, Liu YJ, Iyer VR, and Tucker HO
- Subjects
- Animals, B-Lymphocytes metabolism, Carrier Proteins genetics, Carrier Proteins metabolism, Chromatin Immunoprecipitation, DNA-Binding Proteins, Dendritic Cells cytology, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Gene Expression Profiling, Mice, Mice, Knockout, Mice, Mutant Strains, Nuclear Proteins genetics, Nuclear Proteins metabolism, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Carrier Proteins immunology, Cell Differentiation immunology, Dendritic Cells immunology, Gene Expression Regulation immunology, Gene Regulatory Networks immunology, Nuclear Proteins immunology
- Abstract
The plasmacytoid dendritic cell (pDC) is vital to the coordinated action of innate and adaptive immunity. pDC development has not been unequivocally traced, nor has its transcriptional regulatory network been fully clarified. Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and demonstrate this lineage-specific requirement in the adult organism. Furthermore, we identify BCL11A gene targets and provide a molecular mechanism for its action in pDC commitment. Embryonic germ-line deletion of Bcl11a revealed an absolute cellular, molecular, and functional absence of pDCs in fetal mice. In adults, deletion of Bcl11a in hematopoietic stem cells resulted in perturbed yet continued generation of progenitors, loss of downstream pDC and B-cell lineages, and persisting myeloid, conventional dendritic, and T-cell lineages. Challenge with virus resulted in a marked reduction of antiviral response in conditionally deleted adults. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators, including ID2 and MTG16. Our results identify BCL11A as an essential, lineage-specific factor that regulates pDC development, supporting a model wherein differentiation into pDCs represents a primed "default" pathway for common dendritic cell progenitors.
- Published
- 2014
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20. Bright/Arid3A acts as a barrier to somatic cell reprogramming through direct regulation of Oct4, Sox2, and Nanog.
- Author
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Popowski M, Templeton TD, Lee BK, Rhee C, Li H, Miner C, Dekker JD, Orlanski S, Bergman Y, Iyer VR, Webb CF, and Tucker H
- Subjects
- Animals, Cell Line, Cellular Reprogramming, Cellular Senescence, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins genetics, Homeodomain Proteins genetics, Lewis X Antigen metabolism, Mice, Nanog Homeobox Protein, Octamer Transcription Factor-3 genetics, Promoter Regions, Genetic, Protein Binding, RNA Interference, RNA, Small Interfering metabolism, SOXB1 Transcription Factors genetics, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcriptome, DNA-Binding Proteins metabolism, Homeodomain Proteins metabolism, Octamer Transcription Factor-3 metabolism, SOXB1 Transcription Factors metabolism, Transcription Factors metabolism
- Abstract
We show here that singular loss of the Bright/Arid3A transcription factor leads to reprograming of mouse embryonic fibroblasts (MEFs) and enhancement of standard four-factor (4F) reprogramming. Bright-deficient MEFs bypass senescence and, under standard embryonic stem cell (ESC) culture conditions, spontaneously form clones that in vitro express pluripotency markers, differentiate to all germ lineages, and in vivo form teratomas and chimeric mice. We demonstrate that BRIGHT binds directly to the promoter/enhancer regions of Oct4, Sox2, and Nanog to contribute to their repression in both MEFs and ESCs. Thus, elimination of the BRIGHT barrier may provide an approach for somatic cell reprogramming.
- Published
- 2014
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- View/download PDF
21. Foxp1 maintains hair follicle stem cell quiescence through regulation of Fgf18.
- Author
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Leishman E, Howard JM, Garcia GE, Miao Q, Ku AT, Dekker JD, Tucker H, and Nguyen H
- Subjects
- Animals, Cell Count, Cell Cycle Checkpoints, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p57 metabolism, Embryo, Mammalian cytology, Fibroblast Growth Factors genetics, HEK293 Cells, Humans, Mice, Cell Cycle, Fibroblast Growth Factors metabolism, Forkhead Transcription Factors metabolism, Hair Follicle cytology, Repressor Proteins metabolism, Stem Cells cytology, Stem Cells metabolism
- Abstract
Hair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain- and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.
- Published
- 2013
- Full Text
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22. The BCL11A transcription factor directly activates RAG gene expression and V(D)J recombination.
- Author
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Lee BS, Dekker JD, Lee BK, Iyer VR, Sleckman BP, Shaffer AL 3rd, Ippolito GC, and Tucker PW
- Subjects
- Amino Acid Sequence, Animals, Carrier Proteins analysis, Carrier Proteins genetics, Cell Line, Cells, Cultured, Gene Deletion, Humans, Mice, Mice, Inbred C57BL, Nuclear Proteins analysis, Nuclear Proteins genetics, Precursor Cells, B-Lymphoid metabolism, Promoter Regions, Genetic, Protein Isoforms analysis, Protein Isoforms genetics, Protein Isoforms metabolism, Repressor Proteins, Up-Regulation, Carrier Proteins metabolism, DNA-Binding Proteins genetics, Homeodomain Proteins genetics, Nuclear Proteins metabolism, Transcriptional Activation, V(D)J Recombination
- Abstract
Recombination-activating gene 1 protein (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining (VDJ) segment recombination, an essential process for antigen receptor expression and lymphocyte development. The transcription factor BCL11A is required for B cell development, but its molecular function(s) in B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds the RAG1 promoter and Erag enhancer to activate RAG1 and RAG2 transcription in pre-B cells. We employed BCL11A overexpression with recombination substrates in a cultured pre-B cell line as well as Cre recombinase-mediated Bcl11a(lox/lox) deletion in explanted murine pre-B cells to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination.
- Published
- 2013
- Full Text
- View/download PDF
23. Foxp1/4 control epithelial cell fate during lung development and regeneration through regulation of anterior gradient 2.
- Author
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Li S, Wang Y, Zhang Y, Lu MM, DeMayo FJ, Dekker JD, Tucker PW, and Morrisey EE
- Subjects
- Animals, Blotting, Southern, Cell Differentiation genetics, Cell Differentiation physiology, Chromatin Immunoprecipitation, Forkhead Transcription Factors genetics, Goblet Cells metabolism, Mice, Mice, Inbred C57BL, Mucoproteins genetics, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Polymerase Chain Reaction, Regeneration physiology, Repressor Proteins genetics, Forkhead Transcription Factors metabolism, Lung metabolism, Mucoproteins metabolism, Repressor Proteins metabolism
- Abstract
The molecular pathways regulating cell lineage determination and regeneration in epithelial tissues are poorly understood. The secretory epithelium of the lung is required for production of mucus to help protect the lung against environmental insults, including pathogens and pollution, that can lead to debilitating diseases such as asthma and chronic obstructive pulmonary disease. We show that the transcription factors Foxp1 and Foxp4 act cooperatively to regulate lung secretory epithelial cell fate and regeneration by directly restricting the goblet cell lineage program. Loss of Foxp1/4 in the developing lung and in postnatal secretory epithelium leads to ectopic activation of the goblet cell fate program, in part, through de-repression of the protein disulfide isomerase anterior gradient 2 (Agr2). Forced expression of Agr2 is sufficient to promote the goblet cell fate in the developing airway epithelium. Finally, in a model of lung secretory cell injury and regeneration, we show that loss of Foxp1/4 leads to catastrophic loss of airway epithelial regeneration due to default differentiation of secretory cells into the goblet cell lineage. These data demonstrate the importance of Foxp1/4 in restricting cell fate choices during development and regeneration, thereby providing the proper balance of functional epithelial lineages in the lung.
- Published
- 2012
- Full Text
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24. Recent advances in Ebolavirus vaccine development.
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Richardson JS, Dekker JD, Croyle MA, and Kobinger GP
- Subjects
- Adenoviridae genetics, Animals, Drug Administration Routes, Ebolavirus genetics, Ebolavirus radiation effects, Genetic Vectors, Hemorrhagic Fever, Ebola therapy, Humans, Post-Exposure Prophylaxis, Vaccination, Vaccines, Subunit, Vaccines, Virus-Like Particle, Ebola Vaccines administration & dosage, Ebola Vaccines immunology, Ebola Vaccines therapeutic use, Ebolavirus immunology, Hemorrhagic Fever, Ebola prevention & control
- Abstract
Ebolavirus is a highly infectious pathogen with a case fatality rate as high as 90%. Currently there is a lack of licensed Ebolavirus vaccines as well as pre- and post-exposure treatments. Recent increases in the frequency of natural human Ebolavirus infections and its potential use as a bioterrorism agent makes vaccine development a priority for many nations. Significant progress has been made in understanding the pathogenesis of Ebolavirus infection and several promising vaccine candidates were shown to be successful in protecting NHPs against lethal infection. These include replication-deficient adenovirus vectors, replication-competent VSV, HPIV-3 vectors and virus-like particle preparations. Recent advances in the generation of effective post-exposure immunization strategies highlight the possibility of developing a single dose vaccine that will confer full protection in humans following Ebolavirus exposure. Post-exposure protection is particularly important in outbreak and biodefense settings, as well as clinical and laboratory settings in the case of accidental exposure.
- Published
- 2010
- Full Text
- View/download PDF
25. Drug-virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model.
- Author
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Wonganan P, Zamboni WC, Strychor S, Dekker JD, and Croyle MA
- Subjects
- Adenoviridae genetics, Adenoviridae metabolism, Animals, Antineoplastic Agents, Phytogenic pharmacokinetics, Cytochrome P-450 CYP3A, Disease Models, Animal, Docetaxel, Gene Expression Regulation, Enzymologic drug effects, Liver drug effects, Liver virology, Male, Rats, Rats, Sprague-Dawley, Transaminases blood, Aryl Hydrocarbon Hydroxylases metabolism, Cytochrome P-450 Enzyme Inhibitors, Genetic Vectors genetics, Liver metabolism, Membrane Proteins metabolism, Taxoids pharmacokinetics
- Abstract
Modern cancer therapy combines recombinant viruses with traditional chemotherapeutic agents that are metabolized by hepatic cytochrome P450 3A4 (CYP3A4). A single dose of recombinant adenovirus (Ad) expressing beta-galactosidase (AdlacZ) significantly alters CYP3A2, the correlate of CYP3A4, in rats for 14 days. Recombinant adenovirus expressing human p53 (Adp53) also suppresses CYP3A2. Plasma clearance of docetaxel (DTX) in animals given AdlacZ (3.38+/-0.22 l h(-1) kg(-1)) was significantly lower than that of those given DTX alone (7.35+/-1.22 l h(-1) kg(-1), P
- Published
- 2009
- Full Text
- View/download PDF
26. Influence of method of systemic administration of adenovirus on virus-mediated toxicity: focus on mortality, virus distribution, and drug metabolism.
- Author
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Boquet MP, Wonganan P, Dekker JD, and Croyle MA
- Subjects
- Adenoviridae classification, Alanine Transaminase metabolism, Animals, Aryl Hydrocarbon Hydroxylases metabolism, Aspartate Aminotransferases metabolism, Cytochrome P-450 CYP3A, Cytochrome P450 Family 2, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Gene Expression, Genome, Viral genetics, Humans, Injections, Intravenous, Kidney metabolism, Liver metabolism, Lung metabolism, Male, Membrane Proteins metabolism, Myocardium metabolism, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins administration & dosage, Recombinant Fusion Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Spleen metabolism, Steroid 16-alpha-Hydroxylase metabolism, Time Factors, Transgenes genetics, beta-Galactosidase genetics, Adenoviridae genetics, Recombinant Fusion Proteins metabolism, beta-Galactosidase metabolism
- Abstract
Introduction: Doses of 2 x 10(12) virus particles/kilogram (vp/kg) and higher of recombinant human adenovirus serotype 5 (HAdV-5) given via the tail vein induce significant toxicity and mortality in the rat. This was not observed when doses of 5.7 x 10(12) vp/kg were given through a surgically implanted jugular catheter. Here we assess how the manner by which HAdV-5 is introduced into the systemic circulation affects biodistribution, transgene expression, toxicity and mortality 0.25, 1, and 4 days after treatment in the rat. Animals were given 5.7 x 10(12) vp/kg of HAdV-5 expressing beta-galactosidase or saline through a jugular catheter or by direct tail vein injection., Results: All animals survived after jugular vein dosing. Tail vein injection of HAdV-5 increased the mortality rate to 42% (p< or =0.01). All deaths occurred within 4 h. Animals dosed through the jugular vein had significantly higher levels of transgene expression in the liver and spleen and significantly more viral genomes in these tissues and kidney and lung within the first 24 h of viral infection compared to those dosed by tail vein injection (p< or =0.01). There was no significant difference between the groups thereafter. Samples from animals that died contained even higher levels of viral genomes and serum transaminases were elevated on average by a factor of 4 at the time of death. There was no significant difference between the two dosing methods with respect to changes in hepatic cytochrome P450 expression and activity throughout the study., Conclusion: These findings suggest that the method of systemic administration should be carefully considered when assessing toxicity data and other parameters at early time points after virus administration in the rat and possibly other animal models.
- Published
- 2008
- Full Text
- View/download PDF
27. Controlled inactivation of recombinant viruses with vitamin B2.
- Author
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Callahan SM, Wonganan P, Obenauer-Kutner LJ, Sutjipto S, Dekker JD, and Croyle MA
- Subjects
- Adenoviridae radiation effects, Adenoviridae ultrastructure, Animals, Dependovirus radiation effects, Dependovirus ultrastructure, Genes, Reporter, Humans, Lentivirus radiation effects, Lentivirus ultrastructure, Liver virology, Methoxsalen pharmacology, Microscopy, Electron, Transmission, Rats, beta-Galactosidase biosynthesis, beta-Galactosidase genetics, Adenoviridae drug effects, Antiviral Agents pharmacology, Dependovirus drug effects, Lentivirus drug effects, Photosensitizing Agents pharmacology, Riboflavin pharmacology, Virus Inactivation
- Abstract
Inactivated viruses are important tools for vaccine development and gene transfer. 8-Methoxypsoralen (8-MOP) and long-wavelength ultraviolet irradiation (LWUVI) inactivates many viruses. Toxicity limits its use in animals and humans. Toxicological and photosensitizing properties of riboflavin make it suitable for virus inactivation in preparations for biological use. Viruses expressing beta-galactosidase were mixed with either 8-MOP (1.5mM) or riboflavin (50 microM) and exposed to LWUVI (365 nm) for 2 h. Virus activity was determined by limiting dilution. The half-life of the adenovirus preparation treated with 8-MOP was 8.28 ns(-1) and 36.5 ns(-1) after treatment with riboflavin. Despite the difference in half-life, both preparations were completely inactivated within 45 min. In contrast, the half-lives for adeno-associated virus (AAV) preparations were similar (63 ns(-1) 8-MOP vs. 67 ns(-1) riboflavin). Each AAV preparation was fully inactivated within 90 min. The half-life of lentivirus was 193.4 ns(-1) after treatment with 8-MOP and 208 ns(-1) after exposure to riboflavin. Virus treated with riboflavin was inactivated within 20 min. Virus exposed to 8-MOP was inactivated in 90 min. DNA and RNA viruses can be inactivated by riboflavin and LWUVI and used in physiological systems sensitive to other photochemicals.
- Published
- 2008
- Full Text
- View/download PDF
28. Gene promoter methylation in plasma and sputum increases with lung cancer risk.
- Author
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Belinsky SA, Klinge DM, Dekker JD, Smith MW, Bocklage TJ, Gilliland FD, Crowell RE, Karp DD, Stidley CA, and Picchi MA
- Subjects
- Adult, Aged, Aged, 80 and over, Apoptosis Regulatory Proteins, Calcium-Calmodulin-Dependent Protein Kinases genetics, DNA, Neoplasm blood, DNA, Neoplasm genetics, DNA, Neoplasm isolation & purification, DNA-Binding Proteins genetics, Death-Associated Protein Kinases, Female, Humans, Lung Neoplasms pathology, Middle Aged, O(6)-Methylguanine-DNA Methyltransferase genetics, PAX5 Transcription Factor, Risk Factors, Smoking, Sputum chemistry, Sputum cytology, Survivors, Transcription Factors genetics, Tumor Suppressor Proteins genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, DNA Methylation, Lung Neoplasms genetics, Promoter Regions, Genetic genetics
- Abstract
Purpose: Lung cancer is the leading cause of cancer mortality in the United States, due in part to the lack of a validated and effective screening approach for early detection. The prevalence for methylation of seven and three genes was examined in DNA from sputum and plasma, respectively, from women at different risk for lung cancer., Experimental Design: Lung cancer survivors (n = 56), clinically cancer-free smokers (n = 121), and never smokers (n = 74) comprised the study population. Plasma was collected from all three groups, whereas sputum was collected from lung cancer survivors and smokers., Results: Methylation was detected in plasma DNA from 10 of 74 women who never smoked. Prevalence for methylation of the p16 gene in plasma was highest in lung cancer survivors. Lung cancer survivors showed a significant increase in the odds of having at least one or more genes methylated in plasma (odds ratio, 3.6; 95% confidence interval, 1.9-9.1) than never smokers. The prevalence for methylation of the O(6)-methylguanine-DNA methyltransferase, ras effector homologue 1, death associated protein kinase, and PAX5alpha genes in sputum was significantly higher in lung cancer survivors compared with smokers. Lung cancer survivors had 6.2-fold greater odds (95% confidence interval, 2.1-18.5) for methylation of three or more genes in sputum compared with smokers. Methylation was more commonly detected in sputum than plasma for O(6)-methylguanine-DNA methyltransferase and ras effector homologue 1, but not p16, in lung cancer survivors., Conclusion: Concomitant methylation of multiple gene promoters in sputum is strongly associated with lung cancer risk.
- Published
- 2005
- Full Text
- View/download PDF
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