scholarly journals Functions of c-Jun in Liver and Heart Development

1999 ◽  
Vol 145 (5) ◽  
pp. 1049-1061 ◽  
Author(s):  
Robert Eferl ◽  
Maria Sibilia ◽  
Frank Hilberg ◽  
Andrea Fuchsbichler ◽  
Iris Kufferath ◽  
...  
Keyword(s):  
Heart Development ◽  
Target Genes ◽  
Cell Function ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Neural Crest Cell ◽  
Cell Types ◽  
Keratin 18 ◽  
Nuclear Factor 1 ◽  
Factor C

Mice lacking the AP-1 transcription factor c-Jun die around embryonic day E13.0 but little is known about the cell types affected as well as the cause of embryonic lethality. Here we show that a fraction of mutant E13.0 fetal livers exhibits extensive apoptosis of both hematopoietic cells and hepatoblasts, whereas the expression of 15 mRNAs, including those of albumin, keratin 18, hepatocyte nuclear factor 1, β-globin, and erythropoietin, some of which are putative AP-1 target genes, is not affected. Apoptosis of hematopoietic cells in mutant livers is most likely not due to a cell-autonomous defect, since c-jun−/− fetal liver cells are able to reconstitute all hematopoietic compartments of lethally irradiated recipient mice. A developmental analysis of chimeras showed contribution of c-jun−/− ES cell derivatives to fetal, but not to adult livers, suggesting a role of c-Jun in hepatocyte turnover. This is in agreement with the reduced mitotic and increased apoptotic rates found in primary liver cell cultures derived from c-jun−/− fetuses. Furthermore, a novel function for c-Jun was found in heart development. The heart outflow tract of c-jun−/− fetuses show malformations that resemble the human disease of a truncus arteriosus persistens. Therefore, the lethality of c-jun mutant fetuses is most likely due to pleiotropic defects reflecting the diversity of functions of c-Jun in development, such as a role in neural crest cell function, in the maintenance of hepatic hematopoiesis and in the regulation of apoptosis.

scholarly journals ETO-2 Associates with SCL in Erythroid Cells and Megakaryocytes and Provides Repressor Functions in Erythropoiesis

2005 ◽  
Vol 25 (23) ◽  
pp. 10235-10250 ◽  
Author(s):  
Anna H. Schuh ◽  
Alex J. Tipping ◽  
Allison J. Clark ◽  
Isla Hamlett ◽  
Boris Guyot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Protein Complexes ◽  
Fetal Liver ◽  
Regulation Of Gene Expression ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Erythroid Cells ◽  
Proteomic Approach ◽  
Endogenous Proteins

ABSTRACT Lineage specification and cellular maturation require coordinated regulation of gene expression programs. In large part, this is dependent on the activator and repressor functions of protein complexes associated with tissue-specific transcriptional regulators. In this study, we have used a proteomic approach to characterize multiprotein complexes containing the key hematopoietic regulator SCL in erythroid and megakaryocytic cell lines. One of the novel SCL-interacting proteins identified in both cell types is the transcriptional corepressor ETO-2. Interaction between endogenous proteins was confirmed in primary cells. We then showed that SCL complexes are shared but also significantly differ in the two cell types. Importantly, SCL/ETO-2 interacts with another corepressor, Gfi-1b, in red cells but not megakaryocytes. The SCL/ETO-2/Gfi-1b association is lost during erythroid differentiation of primary fetal liver cells. Genetic studies of erythroid cells show that ETO-2 exerts a repressor effect on SCL target genes. We suggest that, through its association with SCL, ETO-2 represses gene expression in the early stages of erythroid differentiation and that alleviation/modulation of the repressive state is then required for expression of genes necessary for terminal erythroid maturation to proceed.

scholarly journals The role of KMT2D and KDM6A in cardiac development: A cross-species analysis in humans, mice, and zebrafish

2020 ◽  
Author(s):  
Rwik Sen ◽  
Ezra Lencer ◽  
Elizabeth A. Geiger ◽  
Kenneth L. Jones ◽  
Tamim H. Shaikh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Development ◽  
Target Genes ◽  
Cardiac Development ◽  
Heart Defects ◽  
Neural Crest Cell ◽  
Kabuki Syndrome ◽  
Rna Seq ◽  
Wide Range

AbstractCongenital Heart Defects (CHDs) are the most common form of birth defects, observed in 4-10/1000 live births. CHDs result in a wide range of structural and functional abnormalities of the heart which significantly affect quality of life and mortality. CHDs are often seen in patients with mutations in epigenetic regulators of gene expression, like the genes implicated in Kabuki syndrome – KMT2D and KDM6A, which play important roles in normal heart development and function. Here, we examined the role of two epigenetic histone modifying enzymes, KMT2D and KDM6A, in the expression of genes associated with early heart and neural crest cell (NCC) development. Using CRISPR/Cas9 mediated mutagenesis of kmt2d, kdm6a and kdm6al in zebrafish, we show cardiac and NCC gene expression is reduced, which correspond to affected cardiac morphology and reduced heart rates. To translate our results to a human pathophysiological context and compare transcriptomic targets of KMT2D and KDM6A across species, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We compared the human RNA-seq datasets with RNA-seq datasets obtained from mouse and zebrafish. Our comparative interspecies analysis revealed common targets of KMT2D and KDM6A, which are shared between species, and these target genes are reduced in expression in the zebrafish mutants. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early cardiac and overall development that can contribute to the understanding of epigenetic dysregulation in CHDs.

scholarly journals Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 2952-2961 ◽  
Author(s):  
Philip J. S. Stork ◽  
Tara J. Dillon
Keyword(s):  
Map Kinase ◽  
G Protein ◽  
Protein Function ◽  
Cell Function ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Myelogenous Leukemia ◽  
Critical Control Points ◽  
Small G Protein ◽  
Wide Range

AbstractSmall G proteins serve as critical control points in signal transduction, integrating a wide range of stimuli to dictate discrete cellular outcomes. The outcomes of small G-protein signaling can both potentiate and antagonize one another. Studies in hematopoietic cells have uncovered multiple functions for the small G protein, Rap1 (Ras-proximate-1). Because Rap1 can regulate cell proliferation, differentiation, and adhesion through distinct mechanisms, it serves as a paradigm for the need for tight cellular control of small G-protein function. Rap1 has received recent attention for its role in enhancing integrin-dependent signals. This action of Rap1 augments a variety of processes that characterize hematopoietic-cell function, including aggregation, migration, extravasation, and homing to target tissues. Rap1 may also regulate cellular differentiation and proliferation via pathways that are distinct from those mediating adhesion, and involve regulation of the mitogen-activated protein (MAP) kinase or ERK (extracellular signal-regulated kinase) cascade. These actions of Rap1 occur in selected cell types to enhance or diminish ERK signaling, depending on the expression pattern of the MAP kinase kinase kinases of the Raf family: Raf-1 and B-Raf. This review will examine the functions of Rap1 in hematopoietic cells, and focus on 3 cellular scenarios where the multiple actions of Rap1 function have been proposed. Recent studies implicating Rap1 in the maturation of megakaryocytes, the pathogenesis of chronic myelogenous leukemia (CML), and activation of peripheral T cells will receive particular attention.

scholarly journals Heart regeneration: beyond new muscle and vessels

2021 ◽  
Author(s):  
Judy R Sayers ◽  
Paul R Riley
Keyword(s):  
Heart Development ◽  
Cell Function ◽  
Cell Types ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Cardiovascular Tissue ◽  
Function Calls ◽  
Heart Muscle Cells ◽  
System Cell ◽  
Heart Injury

Abstract The most striking consequence of a heart attack is the loss of billions of heart muscle cells, alongside damage to the associated vasculature. The lost cardiovascular tissue is replaced by scar formation, which is non-functional and results in pathological remodelling of the heart and ultimately heart failure. It is, therefore, unsurprising that the heart regeneration field has centred efforts to generate new muscle and blood vessels through targeting cardiomyocyte proliferation and angiogenesis following injury. However, combined insights from embryological studies and regenerative models, alongside the adoption of -omics technology, highlight the extensive heterogeneity of cell types within the forming or re-forming heart and the significant crosstalk arising from non-muscle and non-vessel cells. In this review, we focus on the roles of fibroblasts, immune, conduction system, and nervous system cell populations during heart development and we consider the latest evidence supporting a function for these diverse lineages in contributing to regeneration following heart injury. We suggest that the emerging picture of neurologically, immunologically, and electrically coupled cell function calls for a wider-ranging combinatorial approach to heart regeneration.

Supraphysiological expression of survival motor neuron protein from an adenovirus vector does not adversely affect cell function

2013 ◽  
Vol 91 (4) ◽  
pp. 252-264 ◽  
Author(s):  
Benoit B. Goulet ◽  
Emily R. McFall ◽  
Carmen M. Wong ◽  
Rashmi Kothary ◽  
Robin J. Parks
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Target Genes ◽  
Cell Function ◽  
Muscular Atrophy ◽  
Human Fibroblasts ◽  
Cell Types ◽  
Survival Motor Neuron ◽  
Slight Reduction ◽  
Systemic Delivery

Spinal muscular atrophy (SMA) is the most common inherited neurodegenerative disease that leads to infant mortality. It is caused by mutations in the survival motor neuron (SMN) protein resulting in death of alpha motor neurons. Increasing evidence suggests that several other tissues are also affected in SMA, including skeletal and cardiac muscle, liver, and pancreas, indicating that systemic delivery of therapeutics may be necessary for true disease correction. Due to the natural biodistribution of therapeutics, a level of SMN several-fold above physiological levels can be achieved in some tissues. In this study, we address whether supraphysiological levels of SMN adversely affects cell function. Infection of a variety of cell types with an adenovirus (Ad) vector encoding SMN leads to very high expression, but the resulting protein correctly localizes within the cell, and associates with normal cellular partners. Although SMN affects transcription of certain target genes and can alter the splicing pattern of others, we did not observe any difference in select target gene splicing or expression in cells overexpressing SMN. However, normal human fibroblasts treated with Ad-SMN showed a slight reduction in growth rate, suggesting that certain cell types may be differently impacted by high levels of SMN.

scholarly journals Unveiling the ups and downs of miR-205 in physiology and cancer: transcriptional and post-transcriptional mechanisms

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Elena Ferrari ◽  
Paolo Gandellini
Keyword(s):  
Epithelial Cell ◽  
Target Genes ◽  
Cell Function ◽  
Cell Types ◽  
Future Application ◽  
Transcriptional Level ◽  
Aberrant Expression ◽  
Specific Tumor ◽  
And Function ◽  
Different Cell Types

Abstract miR-205 plays important roles in the physiology of epithelia by regulating a variety of pathways that govern differentiation and morphogenesis. Its aberrant expression is frequently found in human cancers, where it was reported to act either as tumor-suppressor or oncogene depending on the specific tumor context and target genes. miR-205 expression and function in different cell types or processes are the result of the complex balance among transcription, processing and stability of the microRNA. In this review, we summarize the principal mechanisms that regulate miR-205 expression at the transcriptional and post-transcriptional level, with particular focus on the transcriptional relationship with its host gene. Elucidating the mechanisms and factors regulating miR-205 expression in different biological contexts represents a fundamental step for a better understanding of the contribution of such pivotal microRNA to epithelial cell function in physiology and disease, and for the development of modulation strategies for future application in cancer therapy.

scholarly journals Chromatin Modification and Remodeling in Heart Development

2006 ◽  
Vol 6 ◽  
pp. 1851-1861 ◽  
Author(s):  
Paul Delgado-Olguín ◽  
Jun K. Takeuchi ◽  
Benoit G. Bruneau
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Heart Development ◽  
Target Genes ◽  
Chromatin Modification ◽  
Cell Types ◽  
Specific Function ◽  
Tissue Specific ◽  
Mammalian Heart ◽  
Modifying Factors

In organogenesis, cell types are specified from determined precursors as morphogenetic patterning takes place. These events are largely controlled by tissue-specific transcription factors. These transcription factors must function within the context of chromatin to activate or repress target genes. Recent evidence suggests that chromatin-remodeling and -modifying factors may have tissue-specific function. Here we review the potential roles for chromatin-remodeling and -modifying proteins in the development of the mammalian heart.

scholarly journals Long-term erythropoietic repopulating ability of old, young, and fetal stem cells.

1983 ◽  
Vol 157 (5) ◽  
pp. 1496-1504 ◽  
Author(s):  
D E Harrison
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Fetal Liver ◽  
Standard Dose ◽  
Cell Types ◽  
Better Than ◽  
Sublethal Irradiation ◽  
Marrow Cells

It is possible that erythropoietic stem cells do not age. This would mean that stem cells from old donors can function as well as those from young or fetal donors. The competitive repopulation assay has been used to test long-term stem cell function by directly comparing how well competing stem cells repopulate a recipient and produce differentiated cell types. C57BL/6J (B6) mice were used as donors, while recipients and competitors were WBB6F1 hybrids with genetically distinguishable hemoglobin. Lethally irradiated young WBB6F1 recipients were given a mixture of 2.5 X 10(6) cells from B6 old marrow, young marrow, or fetal liver donors; each recipient also received a standard dose of 1 X 10(6) marrow cells from a pool of young WBB6F1 competitors. Surprisingly, the old marrow cells competed the best in repopulating the recipients. This pattern was maintained even after recovery from sublethal irradiation, a treatment that severely stresses stem cells. This stress was demonstrated when sublethal irradiation caused a 20-fold decline in repopulating ability measured using hemoglobin markers, and a 3- to 7-fold decline using chromosome markers. Stem cells from old marrow competed better than young or fetal cells in similar experiments using immunologically crippled recipients or using unirradiated W/Wv recipients that are immunologically intact. In both types of recipients, the advantage of old marrow cells again persisted after recovery from sublethal irradiation. Other genotypes were tested, and marrow cells from old B6CBAF1 donors competed better than those from young donors of that genotype. However, marrow cells from young CBA donors completed better than those from old CBA donors. These results support the hypothesis that stem cells do not age, and suggest that regulatory changes with age promote rapid stem cell repopulation in B6 and B6CBAF1 mice, but inhibit it in CBA mice.

scholarly journals Expression of Thy-1 on human hematopoietic progenitor cells.

1993 ◽  
Vol 177 (5) ◽  
pp. 1331-1342 ◽  
Author(s):  
W Craig ◽  
R Kay ◽  
R L Cutler ◽  
P M Lansdorp
Keyword(s):  
Mononuclear Cells ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Small Subset ◽  
Human Stem Cells ◽  
Long Term Culture ◽  
Cd34 Cells

Expression of Thy-1 on hematopoietic cells from human fetal liver (FL), cord blood (CB), and bone marrow (BM) was studied with a novel anti-Thy-1 antibody, 5E10. Specificity of 5E10 for human Thy-1 was demonstrated by immunoprecipitation of a 25-35-kD molecule, and the sequence of a cDNA that was cloned by immunoselection of COS cells transfected with a cDNA library derived from a 5E10+ cell line. Two- and three-color immunofluorescence staining experiments revealed that the Thy-1 expression is restricted to, an average, 1-4% of FL, CB, and BM cells, and binding to these cell types is essentially restricted to a very small subset of lymphoid cells and approximately 25% of CD34+ cells. Thy-1+ CD34+ cells were further characterized as CD38lo/CD45RO+/CD45RA-/CD71lo/c-kit(lo) and rhodamine 123dull. When CD34+ cells were sorted on the basis of Thy-1 expression, the majority of clonogenic cells were recovered in the CD34+Thy-1- fraction, whereas the majority of cells capable of producing myeloid colonies after 5-8 wk of long-term culture (long-term culture initiating cells) were recovered in the Thy-1+CD34+ fraction. In addition to CD34+ cells, Thy-1 was found to be expressed on a variable, very small number (< 1%) of CD34- mononuclear cells in BM, CB, and peripheral blood that were further characterized as CD3+ CD4+ lymphocytes. The restricted expression of Thy-1 on primitive hematopoietic cells is in agreement with a previous report (Baum et al., 1992. Proc. Natl. Acad. Sci. USA. 89:2804) in which Thy-1 expression was used to enrich for primitive hematopoietic cells from fetal tissue. Compared with those previous studies, we found Thy-1 expression on a larger proportion of CD34+ cells (25% in our study vs. 5% in Baum et al.) and furthermore performed studies on Thy-1 expression on CD34+ cells from CB, FL, and BM in relation to markers that are known to be differentially expressed on hematopoietic cells. Taken together our results indicate that Thy-1-specific antibody 5E10 is an attractive tool for further studies on the biology and purification of human stem cells.

scholarly journals Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5783-5792 ◽  
Author(s):  
Josette-Renée Landry ◽  
Nicolas Bonadies ◽  
Sarah Kinston ◽  
Kathy Knezevic ◽  
Nicola K. Wilson ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Fetal Liver ◽  
Lymphoblastic Leukemia ◽  
Severe Combined Immunodeficiency ◽  
Hematopoietic Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Proximal Promoter ◽  
Hematopoietic Stem ◽  
Conserved Noncoding Elements

Abstract The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.

Sign in / Sign up

Export Citation Format

Share Document