scholarly journals Hif-1α regulates differentiation of limb bud mesenchyme and joint development

2007 ◽  
Vol 177 (3) ◽  
pp. 451-464 ◽  
Author(s):  
Sylvain Provot ◽  
Dawn Zinyk ◽  
Yasemin Gunes ◽  
Richa Kathri ◽  
Quynh Le ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fetal Development ◽  
Adaptive Response ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Low Oxygen ◽  
Joint Development ◽  
Low Oxygen Tension ◽  
Development And Differentiation

Recent evidence suggests that low oxygen tension (hypoxia) may control fetal development and differentiation. A crucial mediator of the adaptive response of cells to hypoxia is the transcription factor Hif-1α. In this study, we provide evidence that mesenchymal condensations that give origin to endochondral bones are hypoxic during fetal development, and we demonstrate that Hif-1α is expressed and transcriptionally active in limb bud mesenchyme and in mesenchymal condensations. To investigate the role of Hif-1α in mesenchymal condensations and in early chondrogenesis, we conditionally inactivated Hif-1α in limb bud mesenchyme using a Prx1 promoter-driven Cre transgenic mouse. Conditional knockout of Hif-1α in limb bud mesenchyme does not impair mesenchyme condensation, but alters the formation of the cartilaginous primordia. Late hypertrophic differentiation is also affected as a result of the delay in early chondrogenesis. In addition, mutant mice show a striking impairment of joint development. Our study demonstrates a crucial, and previously unrecognized, role of Hif-1α in early chondrogenesis and joint formation.

Pax-3 is necessary for migration but not differentiation of limb muscle precursors in the mouse

Development ◽  
1996 ◽  
Vol 122 (3) ◽  
pp. 1017-1027 ◽  
Author(s):  
G. Daston ◽  
E. Lamar ◽  
M. Olivier ◽  
M. Goulding
Keyword(s):  
Transcription Factor ◽  
Muscle Differentiation ◽  
Precursor Cells ◽  
Limb Bud ◽  
Limb Muscle ◽  
Paired Domain ◽  
Lateral Edge ◽  
Limb Muscles ◽  
In Cells

The limb muscles of vertebrates are derived from precursor cells that migrate from the lateral edge of the dermomyotome into the limb bud. Previous studies have shown that the paired domain-containing transcription factor Pax-3 is expressed in the limb in cells that are precursors for limb muscles (Williams, B. and Ordahl, C.P. (1994) Development 120, 785–796). In splotch (Pax-3-) embryos, the limb muscles fail to develop and cells expressing Pax-3 are no longer found in the limb. In this paper we have analyzed the role of Pax-3 in the migration and subsequent differentiation of limb muscle precursors. By labeling somites adjacent to the prospective forelimb with the lipophilic dye DiI, we have shown that cells derived from these somites do not migrate into the limbs of splotch mice. The failure of limb muscle precursors to invade the limb in splotch mice is associated with the absence of c-met expression in premigratory cells, together with a change in the morphology of the ventral dermomyotome. In addition, we have shown the lateral half of somites derived from day E9.25 splotch embryos can undergo muscle differentiation when grafted into the limb bud stage 20 chick host embryos. Our results indicate that Pax-3 regulates the migration of limb muscle precursors into the limb and is not required for cells in the lateral somite to differentiate into muscle.

scholarly journals Trajectory Shifts in Interdisciplinary Research of the Aryl Hydrocarbon Receptor—A Personal Perspective on Thymus and Skin

2021 ◽  
Vol 22 (4) ◽  
pp. 1844
Author(s):  
Charlotte Esser
Keyword(s):  
Transcription Factor ◽  
Immune System ◽  
Environmental Pollution ◽  
Aryl Hydrocarbon Receptor ◽  
Interdisciplinary Research ◽  
Adaptive Response ◽  
Personal Perspective ◽  
Aryl Hydrocarbon

Identifying historical trajectories is a useful exercise in research, as it helps clarify important, perhaps even “paradigmatic”, shifts in thinking and moving forward in science. In this review, the development of research regarding the role of the transcription factor “aryl hydrocarbon receptor” (AHR) as a mediator of the toxicity of environmental pollution towards a link between the environment and a healthy adaptive response of the immune system and the skin is discussed. From this fascinating development, the opportunities for targeting the AHR in the therapy of many diseases become clear.

scholarly journals Sirt6 Regulates the Development of Medullary Thymic Epithelial Cells and Contributes to the Establishment of Central Immune Tolerance

2021 ◽  
Vol 9 ◽  
Author(s):  
Qian Zhang ◽  
Zhanfeng Liang ◽  
Jiayu Zhang ◽  
Tong Lei ◽  
Xue Dong ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Conditional Knockout ◽  
Thymic Epithelial Cells ◽  
Reduced Body ◽  
Epigenetic Regulator ◽  
Development And Differentiation ◽  
Medullary Thymic Epithelial Cells ◽  
Proliferation Ability ◽  
Made In

Although some advances have been made in understanding the molecular regulation of mTEC development, the role of epigenetic regulators in the development and maturation of mTEC is poorly understood. Here, using the TEC-specific Sirt6 knockout mice, we found the deacetylase Sirtuin 6 (Sirt6) is essential for the development of functionally competent mTECs. First of all, TEC-specific Sirt6 deletion dramatically reduces the mTEC compartment, which is caused by reduced DNA replication and subsequent impaired proliferation ability of Sirt6-deficient mTECs. Secondly, Sirt6 deficiency specifically accelerates the differentiation of mTECs from CD80–Aire– immature population to CD80+Aire– intermediate mature population by promoting the expression of Spib. Finally, Sirt6 ablation in TECs markedly interferes the proper expression of tissue-restricted antigens (TRAs) and impairs the development of thymocytes and nTreg cells. In addition, TEC conditional knockout of Sirt6 results in severe autoimmune disease manifested by reduced body weight, the infiltration of lymphocytes and the presence of autoantibodies. Collectively, this study reveals that the expression of epigenetic regulator Sirt6 in TECs is crucial for the development and differentiation of mTECs, which highlights the importance of Sirt6 in the establishment of central immune tolerance.

Help Me Breathe Easy

2021 ◽  
pp. 361-363
Author(s):  
Deepa R.
Keyword(s):  
Oxygen Tension ◽  
Human Body ◽  
Adaptive Response ◽  
Pathological Condition ◽  
Tissue Level ◽  
The Body ◽  
Low Oxygen ◽  
Hypoxic Conditions ◽  
Low Oxygen Tension ◽  
Life Threatening

Oxygen is one of the most important necessities in our life such as air, water, food and vitamins. Deficiency in either the delivery or the utilization of oxygen at the tissue level leading to changes in functions, metabolisms and structures of cells and tissues of the body. A variety of pathological condition exist where the affected tissues are hypoxic or exhibit a low oxygen tension. Each of the billions of cells that make up the human body requires an adequate supply of oxygen for survival and optimum functioning. Cells and organisms are able to trigger an adaptive response to hypoxic conditions that is aimed to help them to cope with the life threatening conditions.

scholarly journals Evidence for the Involvement of Diacylglycerol Kinase in the Activation of Hypoxia-inducible Transcription Factor 1 by Low Oxygen Tension

2001 ◽  
Vol 276 (13) ◽  
pp. 10548-10555 ◽  
Author(s):  
Julián Aragonés ◽  
David R. Jones ◽  
Silvia Martı́n ◽  
Miguel Angel San Juan ◽  
Arántzazu Alfranca ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Oxygen Tension ◽  
Diacylglycerol Kinase ◽  
Low Oxygen ◽  
Low Oxygen Tension ◽  
Transcription Factor 1

scholarly journals Conditional Mutagenesis of Gata6 in SF1-Positive Cells Causes Gonadal-Like Differentiation in the Adrenal Cortex of Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (5) ◽  
pp. 1754-1767 ◽  
Author(s):  
Marjut Pihlajoki ◽  
Elisabeth Gretzinger ◽  
Rebecca Cochran ◽  
Antti Kyrönlahti ◽  
Anja Schrade ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adrenal Cortex ◽  
Adrenal Glands ◽  
Conditional Knockout ◽  
Hormonal Changes ◽  
Corticosterone Secretion ◽  
Steroidogenic Cell ◽  
Nulliparous Female ◽  
And Function

Abstract Transcription factor GATA6 is expressed in the fetal and adult adrenal cortex and has been implicated in steroidogenesis. To characterize the role of transcription factor GATA6 in adrenocortical development and function, we generated mice in which Gata6 was conditionally deleted using Cre-LoxP recombination with Sf1-cre. The adrenal glands of adult Gata6 conditional knockout (cKO) mice were small and had a thin cortex. Cytomegalic changes were evident in fetal and adult cKO adrenal glands, and chromaffin cells were ectopically located at the periphery of the glands. Corticosterone secretion in response to exogenous ACTH was blunted in cKO mice. Spindle-shaped cells expressing Gata4, a marker of gonadal stroma, accumulated in the adrenal subcapsule of Gata6 cKO mice. RNA analysis demonstrated the concomitant upregulation of other gonadal-like markers, including Amhr2, in the cKO adrenal glands, suggesting that GATA6 inhibits the spontaneous differentiation of adrenocortical stem/progenitor cells into gonadal-like cells. Lhcgr and Cyp17 were overexpressed in the adrenal glands of gonadectomized cKO vs control mice, implying that GATA6 also limits sex steroidogenic cell differentiation in response to the hormonal changes that accompany gonadectomy. Nulliparous female and orchiectomized male Gata6 cKO mice lacked an adrenal X-zone. Microarray hybridization identified Pik3c2g as a novel X-zone marker that is downregulated in the adrenal glands of these mice. Our findings offer genetic proof that GATA6 regulates the differentiation of steroidogenic progenitors into adrenocortical cells.

scholarly journals The Nuclear Orphan Receptor COUP-TFII Is Required for Limb and Skeletal Muscle Development

2004 ◽  
Vol 24 (24) ◽  
pp. 10835-10843 ◽  
Author(s):  
Christopher T. Lee ◽  
Luoping Li ◽  
Norio Takamoto ◽  
James F. Martin ◽  
Francesco J. DeMayo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Embryonic Lethality ◽  
Conditional Knockout ◽  
Limb Bud ◽  
Orphan Receptor ◽  
Skeletal Muscle Development ◽  
Early Embryonic Lethality ◽  
Nuclear Orphan Receptor

ABSTRACT The nuclear orphan receptor COUP-TFII is widely expressed in multiple tissues and organs throughout embryonic development, suggesting that COUP-TFII is involved in multiple aspects of embryogenesis. Because of the early embryonic lethality of COUP-TFII knockout mice, the role of COUP-TFII during limb development has not been determined. COUP-TFII is expressed in lateral plate mesoderm of the early embryo prior to limb bud formation. In addition, COUP-TFII is also expressed in the somites and skeletal muscle precursors of the limbs. Therefore, in order to study the potential role of COUP-TFII in limb and skeletal muscle development, we bypassed the early embryonic lethality of the COUP-TFII mutant by using two methods. First, embryonic chimera analysis has revealed an obligatory role for COUP-TFII in limb bud outgrowth since mutant cells are unable to contribute to the distally growing limb mesenchyme. Second, we used a conditional-knockout approach to ablate COUP-TFII specifically in the limbs. Loss of COUP-TFII in the limbs leads to hypoplastic skeletal muscle development, as well as shorter limbs. Taken together, our results demonstrate that COUP-TFII plays an early role in limb bud outgrowth but not limb bud initiation. Also, COUP-TFII is required for appropriate development of the skeletal musculature of developing limbs.

scholarly journals POS0002 PI16 REPRESSES FOXP3 EXPRESSION IN T REGULATORY CELLS AND EXACERBATES AUTOIMMUNE ARTHRITIS VIA INHIBITING THE K48-LINKED POLYUBIQUITIN DEGRADATION OF BMI-1

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 203.2-203
Author(s):  
S. Lin ◽  
X. Gu ◽  
F. Wang ◽  
W. Tan
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Histone Modification ◽  
Disease Progression ◽  
Synovial Tissue ◽  
Foxp3 Expression ◽  
Conditional Knockout ◽  
Autoimmune Arthritis ◽  
Peptidase Inhibitor

Background:Regulatory T cells (Tregs) play an essential role in maintaining self-tolerance and immune homeostasis. Abnormalities in the quantity or function of Treg cells are believed in RA patients, contributing to the inability to suppress autoimmunity and proinflammatory cytokines. Forkhead box P3 (Foxp3) is a crucial transcription factor for the development and differentiation of Tregs. How Tregs lose Foxp3 expression under inflammatory milieu remains largely unknown. Peptidase inhibitor 16 (PI16) is a member of the CAP (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1) protein family and its function are largely poor understood. In a genome-wide expression profiling study for identifying human Foxp3 target genes revealed PI16 was expressed on the cell surface of >80% of resting human CD25+ Foxp3+ Tregs. In the inflamed joint of juvenile idiopathic arthritis revealed a low number of PI16+ Tregs but high number of Th17 cells. However, little is known the function role of PI16 on Tregs or on RA development.Objectives:To investigate the role of peptidase inhibitor 16 (PI16) on the key T regulatory (Tregs) cells transcription factor Foxp3 expression and on the development of autoimmune arthritis.Methods:The expression of PI16 in blood, synovial fluid, inflamed joints were examined in Rheumatoid arthritis (RA) patients and in arthritic mice. Arthritis symptom, histological features and Foxp3 expression in PI16 transgenic (PI16Tg) arthritic mice were examined. Posttranslational mechanisms on PI16-mediated Foxp3 expression were analyzed. The specific role PI16 on Foxp3 expression was validated in conditional knockout (KO) mice.Results:The expression of PI16 was significantly increased in PBMC, serum, synovial tissue from RA patients or arthritic mice compared with controls. PI16Tg arthritic mice exhibited obvious inflammation, synovial hyperplasia and articular cartilage destruction in the joints compared with those in wild-type mice (WT) arthritic mice.Foxp3 is downregulated in splenic T cells and synovial tissue from PI16Tg arthritic mice. Naïve T cells derived from PI16Tg arthritic mice showed the decreased capacity to differentiate into Tregs. Polycomb-group (PcG) proteins complex molecule of Bmi-1 was significant increase in Tregs and joint tissue from PI16Tg arthritic mice. A direct interaction between 1-95AA domains of PI16 and 169 and 436 domains of Bmi-1 in Tregs promoter was observed. The binding of PI16 with Bmi-1 in the Foxp3 promoter inhibit the K48-linked polyubiquitin degradation of Bmi-1 at lysine site 72 and 153 region, which prompts the repressive histone modification of H3K27me3 and H2AK119ub, and inhibits the active histone modification of H3K4me3. Furthermore, conditional knockout of PI16 in Tregs retarded Foxp3 loss and blunted disease progression in experimental arthritis.Conclusion:PI16 represses Foxp3 expression by mediating histone modification via inhibiting K48-linked polyubiquitin degradation of Bmi-1 in Foxp3 promoter, contributing to disease progression in arthritic mice.Disclosure of Interests:None declared.

The role of transcription factor Egr‐1 in IL‐1 up‐regulation of tubular CD44 expression

Nephrology ◽  
2000 ◽  
Vol 5 (3) ◽  
pp. A92-A92
Author(s):  
Takazoe K ◽  
Foti R ◽  
Hurst La ◽  
Atkins Rc ◽  
Nikolic‐Paterson DJ.
Keyword(s):  
Transcription Factor ◽  
Cd44 Expression
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