scholarly journals Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage

2008 ◽  
Vol 205 (3) ◽  
pp. 611-624 ◽  
Author(s):  
Alan B. Cantor ◽  
Hiromi Iwasaki ◽  
Yojiro Arinobu ◽  
Tyler B. Moran ◽  
Hirokazu Shigematsu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mast Cell ◽  
Cell Fate ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Transcriptional Networks ◽  
Physical Interaction ◽  
Gata Factor ◽  
Down Regulation ◽  
Enhancer Element

The zinc finger transcription factor GATA-1 requires direct physical interaction with the cofactor friend of GATA-1 (FOG-1) for its essential role in erythroid and megakaryocytic development. We show that in the mast cell lineage, GATA-1 functions completely independent of FOG proteins. Moreover, we demonstrate that FOG-1 antagonizes the fate choice of multipotential progenitor cells for the mast cell lineage, and that its down-regulation is a prerequisite for mast cell development. Remarkably, ectopic expression of FOG-1 in committed mast cell progenitors redirects them into the erythroid, megakaryocytic, and granulocytic lineages. These lineage switches correlate with transcriptional down-regulation of GATA-2, an essential mast cell GATA factor, via switching of GATA-1 for GATA-2 at a key enhancer element upstream of the GATA-2 gene. These findings illustrate combinatorial control of cell fate identity by a transcription factor and its cofactor, and highlight the role of transcriptional networks in lineage determination. They also provide evidence for lineage instability during early stages of hematopoietic lineage commitment.

Development of hematopoietic cells lacking transcription factor GATA-1

Development ◽  
1995 ◽  
Vol 121 (1) ◽  
pp. 163-172 ◽  
Author(s):  
L. Pevny ◽  
C.S. Lin ◽  
V. D'Agati ◽  
M.C. Simon ◽  
S.H. Orkin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mast Cell ◽  
Cell Differentiation ◽  
Mast Cells ◽  
Blood Cell ◽  
Embryonic Stem ◽  
Sequence Motif ◽  
Erythroid Cells ◽  
Gata Factor

GATA-1 is a zinc-finger transcription factor believed to play an important role in gene regulation during the development of erythroid cells, megakaryocytes and mast cells. Other members of the GATA family, which can bind to the same DNA sequence motif, are co-expressed in several of these hemopoietic lineages, raising the possibility of overlap in function. To examine the specific roles of GATA-1 in hematopoietic cell differentiation, we have tested the ability of embryonic stem cells, carrying a targeted mutation in the X-linked GATA-1 gene, to contribute to various blood cell types when used to produce chimeric embryos or mice. Previously, we reported that GATA-1- mutant cells failed to contribute to the mature red blood cell population, indicating a requirement for this factor at some point in the erythroid lineage (L. Pevny et al., (1991) Nature 349, 257–260). In this study, we have used in vitro colony assays to identify the stage at which mutant erythroid cells are affected, and to examine the requirement for GATA-1 in other lineages. We found that the development of erythroid progenitors in embryonic yolk sacs was unaffected by the mutation, but that the cells failed to mature beyond the proerythroblast stage, an early point in terminal differentiation. GATA-1- colonies contained phenotypically normal macrophages, neutrophils and megakaryocytes, indicating that GATA-1 is not required for the in vitro differentiation of cells in these lineages. GATA-1- megakaryocytes were abnormally abundant in chimeric fetal livers, suggesting an alteration in the kinetics of their formation or turnover. The lack of a block in terminal megakaryocyte differentiation was shown by the in vivo production of platelets expressing the ES cell-derived GPI-1C isozyme. The role of GATA-1 in mast cell differentiation was examined by the isolation of clonal mast cell cultures from chimeric fetal livers. Mutant and wild-type mast cells displayed similar growth and histochemical staining properties after culture under conditions that promote the differentiation of cells resembling mucosal or serosal mast cells. Thus, the mast and megakaryocyte lineages, in which GATA-1 and GATA-2 are co-expressed, can complete their maturation in the absence of GATA-1, while erythroid cells, in which GATA-1 is the predominant GATA factor, are blocked at a relatively early stage of maturation.

pha-4 is Ce-fkh-1, a fork head/HNF-3alpha, beta, gamma homolog that functions in organogenesis of the C. elegans pharynx

Development ◽  
1998 ◽  
Vol 125 (12) ◽  
pp. 2171-2180 ◽  
Author(s):  
J.M. Kalb ◽  
K.K. Lau ◽  
B. Goszczynski ◽  
T. Fukushige ◽  
D. Moons ◽  
...  
Keyword(s):  
Early Stage ◽  
Sequence Similarity ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Specific Gene ◽  
Gata Factor ◽  
Enhancer Element ◽  
C Elegans ◽  
Fork Head ◽  
Organ Identity

The C. elegans Ce-fkh-1 gene has been cloned on the basis of its sequence similarity to the winged-helix DNA binding domain of the Drosophila fork head and mammalian HNF-3alpha, beta, gamma genes, and mutations in the zygotically active pha-4 gene have been shown to block formation of the pharynx (and rectum) at an early stage in embryogenesis. In the present paper, we show that Ce-fkh-1 and pha-4 are the same gene. We show that PHA-4 protein is present in nuclei of essentially all pharyngeal cells, of all five cell types. PHA-4 protein first appears close to the point at which a cell lineage will produce only pharyngeal cells, independently of cell type. We show that PHA-4 binds directly to a ‘pan-pharyngeal enhancer element’ previously identified in the promoter of the pharyngeal myosin myo-2 gene; in transgenic embryos, ectopic PHA-4 activates ectopic myo-2 expression. We also show that ectopic PHA-4 can activate ectopic expression of the ceh-22 gene, a pharyngeal-specific NK-2-type homeodomain protein previously shown to bind a muscle-specific enhancer near the PHA-4 binding site in the myo-2 promoter. We propose that it is the combination of pha-4 and regulatory molecules such as ceh-22 that produces the specific gene expression patterns during pharynx development. Overall, pha-4 can be described as an ‘organ identity factor’, completely necessary for organ formation, present in all cells of the organ from the earliest stages, capable of integrating upstream developmental pathways (in this case, the two distinct pathways that produce the anterior and posterior pharynx) and participating directly in the transcriptional regulation of organ specific genes. Finally, we note that the distribution of PHA-4 protein in C. elegans embryos is remarkably similar to the distribution of the fork head protein in Drosophila embryos: high levels in the foregut/pharynx and hindgut/rectum; low levels in the gut proper. Moreover, we show that pha-4 expression in the C. elegans gut is regulated by elt-2, a C. elegans gut-specific GATA-factor and possible homolog of the Drosophila gene serpent, which influences fork head expression in the fly gut. Overall, our results provide evidence for a highly conserved pathway regulating formation of the digestive tract in all (triploblastic) metazoa.

scholarly journals Dissecting Hes-centered transcriptional networks in neural stem cell maintenance and tumorigenesis in Drosophila

2020 ◽  
Author(s):  
Srivathsa S. Magadi ◽  
Chrysanthi Voutyraki ◽  
Gerasimos Anagnostopoulos ◽  
Evanthia Zacharioudaki ◽  
Ioanna K. Poutakidou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Nervous System ◽  
Transcription Factor ◽  
Stem Cell ◽  
Neural Stem Cells ◽  
Cell Fate ◽  
Asymmetric Cell Division ◽  
Transcriptional Networks ◽  
Malignant Tumours ◽  
Stem Cell Maintenance

ABSTRACTNeural stem cells divide during embryogenesis and post embryonic development to generate the entire complement of neurons and glia in the nervous system of vertebrates and invertebrates. Studies of the mechanisms controlling the fine balance between neural stem cells and more differentiated progenitors have shown that in every asymmetric cell division progenitors send a Delta-Notch signal back to their sibling stem cells. Here we show that excessive activation of Notch or overexpression of its direct targets of the Hes family causes stem-cell hyperplasias in the Drosophila larval central nervous system, which can progress to malignant tumours after allografting to adult hosts. We combined transcriptomic data from these hyperplasias with chromatin occupancy data for Dpn, a Hes transcription factor, to identify genes regulated by Hes factors in this process. We show that the Notch/Hes axis represses a cohort of transcription factor genes. These are excluded from the stem cells and promote early differentiation steps, most likely by preventing the reversion of immature progenitors to a stem-cell fate. Our results suggest that Notch signalling sets up a network of mutually repressing stemness and anti-stemness transcription factors, which include Hes proteins and Zfh1, respectively. This mutual repression ensures robust transition to neuronal and glial differentiation and its perturbation can lead to malignant transformation.

scholarly journals Intestinal Neurod1 expression impairs paneth cell differentiation and promotes enteroendocrine lineage specification

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hui Joyce Li ◽  
Subir K. Ray ◽  
Ning Pan ◽  
Jody Haigh ◽  
Bernd Fritzsch ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Intestinal Epithelial Cells ◽  
Paneth Cell ◽  
Substantial Reduction ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Intestinal Epithelial ◽  
Conditional Expression

AbstractTranscription factor Neurod1 is required for enteroendocrine progenitor differentiation and maturation. Several earlier studies indicated that ectopic expression of Neurod1 converted non- neuronal cells into neurons. However, the functional consequence of ectopic Neurod1 expression has not been examined in the GI tract, and it is not known whether Neurod1 can similarly switch cell fates in the intestine. We generated a mouse line that would enable us to conditionally express Neurod1 in intestinal epithelial cells at different stages of differentiation. Forced expression of Neurod1 throughout intestinal epithelium increased the number of EECs as well as the expression of EE specific transcription factors and hormones. Furthermore, we observed a substantial reduction of Paneth cell marker expression, although the expressions of enterocyte-, tuft- and goblet-cell specific markers are largely not affected. Our earlier study indicated that Neurog3+ progenitor cells give rise to not only EECs but also Goblet and Paneth cells. Here we show that the conditional expression of Neurod1 restricts Neurog3+ progenitors to adopt Paneth cell fate, and promotes more pronounced EE cell differentiation, while such effects are not seen in more differentiated Neurod1+ cells. Together, our data suggest that forced expression of Neurod1 programs intestinal epithelial cells more towards an EE cell fate at the expense of the Paneth cell lineage and the effect ceases as cells mature to EE cells.

scholarly journals PAG-3, a Zn-finger transcription factor, determines neuroblast fate in C. elegans

Development ◽  
2002 ◽  
Vol 129 (7) ◽  
pp. 1763-1774 ◽  
Author(s):  
Scott Cameron ◽  
Scott G. Clark ◽  
Joan B. McDermott ◽  
Eric Aamodt ◽  
H. Robert Horvitz
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Daughter Cell ◽  
Cell Lineage ◽  
Blast Cell ◽  
Cell Fates ◽  
Zinc Finger Transcription Factor ◽  
C Elegans ◽  
Mother Cells

During Caenorhabditis elegans development, the patterns of cell divisions, cell fates and programmed cell deaths are reproducible from animal to animal. In a search for mutants with abnormal patterns of programmed cell deaths in the ventral nerve cord, we identified mutations in the gene pag-3, which encodes a zinc-finger transcription factor similar to the mammalian Gfi-1 and Drosophila Senseless proteins. In pag-3 mutants, specific neuroblasts express the pattern of divisions normally associated with their mother cells, producing with each reiteration an abnormal anterior daughter neuroblast and an extra posterior daughter cell that either terminally differentiates or undergoes programmed cell death, which accounts for the extra cell corpses seen in pag-3 mutants. In addition, some neurons do not adopt their normal fates in pag-3 mutants. The phenotype of pag-3 mutants and the expression pattern of the PAG-3 protein suggest that in some lineages pag-3 couples the determination of neuroblast cell fate to subsequent neuronal differentiation. We propose that pag-3 counterparts in other organisms determine blast cell identity and for this reason may lead to cell lineage defects and cell proliferation when mutated.

The Ordered Expression of Transcription Factors Directs Hierarchical Lineage Specification of Eosinophils, Basophils and Mast Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 224-224
Author(s):  
Hiromi Iwasaki ◽  
Yojiro Arinobu ◽  
Shin-ichi Mizuno ◽  
Hirokazu Shigematsu ◽  
Kiyoshi Takatsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Mast Cell ◽  
Cell Fate ◽  
Gene Expression Analysis ◽  
Lineage Specification ◽  
Retroviral Transduction ◽  
Cell Lineages ◽  
Stem And Progenitor Cells ◽  
Eosinophil Colonies

Abstract Here we show that eosinophil progenitors (EoPs) and basophil/mast cell progenitors (BMCPs) are prospectively isolatable in normal hematopoiesis, and that their lineage decisions are regulated principally by GATA-2 and C/EBPα. These progenitors were isolated downstream of granulocyte/monocyte progenitors (GMPs), and BMCPs further generated monopotent basophil progenitors (BaPs) and mast cell progenitors (MCPs). Gene expression analysis showed that neither GATA-1 nor GATA-2 was expressed in GMPs, whereas both of them were upregulated in EoPs, BMCPs, BaPs and MCPs. Importantly, C/EBPα was expressed in EoPs and BaPs as well as GMPs, but was downregulated in BMCPs and MCPs. We have reported that GATA-1 is critical primarily for megakaryocyte/erythrocyte commitment or conversion of stem and progenitor cells. We therefore focused on GATA-2 and C/EBPα functions in this study. Since both EoPs and BaPs co-expressed GATA-2 and C/EBPα while GMPs expressed only C/EBPα, we first transduced GATA-2 into GMPs via a GFP-tagged retrovirus. Strikingly, all GATA-2+ GMPs gave rise to pure eosinophil colonies but not basophil colonies, indicating that enforced GATA-2 can instruct GMPs to become EoPs. Next, since BMCPs only expressed GATA-2 but not C/EBPα, we maintained the expression of C/EBPα in GMPs by retroviral transduction. Interestingly, the sustained expression of C/EBPα blocked basophil/mast cell differentiation from GMPs, indicating that C/EBPα downregulation is required for GMPs to choose the basophil/mast cell fate. As a reciprocal experiment, we conditionally disrupted C/EBPα gene at the level of GMPs by retrovirally transducing Cre gene into GMPs purified from mice in which C/EBPα gene is flanked by loxP sequences (floxed: F). The frequency of mast cell read-out from C/EBPα-disrupted GMPs was 5-fold higher than that from C/EBPα F/F (Cre−) GMPs. C/EBPα-disrupted GMPs, however, did not give rise to BaPs. Furthermore, MCPs transduced with C/EBPα were converted into BaPs. Thus, C/EBPα is required to be reactivated during transition from BMCPs to BaPs. We further tested their interplay in specification of these lineages by using common lymphoid progenitors (CLPs), which do not express GATA-2 or C/EBPα. We enforced the expression of each transcription factor in CLPs in different orders by using the two-step retroviral transduction system. Interestingly, C/EBPα transduction reprogrammed CLPs into GM lineages, and subsequently-transduced GATA-2 instructed C/EBPα + CLPs to select the eosinophil fate. Next, we switched the order of transduction. Strikingly, GATA-2 transduction converted CLPs into BMCPs, and subsequently-transduced C/EBPα specified GATA-2+ CLPs to become BaPs. Thus, at the branchpoint for EoPs and BMCPs, GATA-2 upregulation instructed EoP development if C/EBPα was present, whereas it instructed BMCP development if C/EBPα was absent. After the BMCP stage, C/EBPα had to remain suppressed for MCP development, whereas BaPs developed by C/EBPα reactivation. These data collectively suggest that the order of expression of GATA-2 and C/EBPα is critical for their interplay to selectively activate developmental programs for the eosinophil, the basophil and the mast cell lineages.

scholarly journals LMO2 is essential to maintain the ability of progenitors to differentiate into T-cell lineage in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Ken-ichi Hirano ◽  
Hiroyuki Hosokawa ◽  
Maria Koizumi ◽  
Yusuke Endo ◽  
Takashi Yahata ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cell ◽  
B Cells ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Massive Cell Death ◽  
Direct Binding ◽  
Massive Cell

Notch signaling primarily determines T-cell fate. However, the molecular mechanisms underlying the maintenance of T-lineage potential in pre-thymic progenitors remain unclear. Here, we established two murine Ebf1-deficient pro-B cell lines, with and without T-lineage potential. The latter expressed lower levels of Lmo2; their potential was restored via ectopic expression of Lmo2. Conversely, the CRISPR/Cas9-mediated deletion of Lmo2 resulted in the loss of the T-lineage potential. Introduction of Bcl2 rescued massive cell death of Notch-stimulated pro-B cells without efficient LMO2-driven Bcl11a expression but was not sufficient to retain their T-lineage potential. Pro-B cells without T-lineage potential failed to activate Tcf7 due to DNA methylation; Tcf7 transduction restored this capacity. Moreover, direct binding of LMO2 to the Bcl11a and Tcf7 loci was observed. Altogether, our results highlight LMO2 as a crucial player in the survival and maintenance of T-lineage potential in T-cell progenitors via the regulation of the expression of Bcl11a and Tcf7.

The zinc finger proteins Pannier and GATA4 function as cardiogenic factors in Drosophila

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5679-5688 ◽  
Author(s):  
K. Gajewski ◽  
N. Fossett ◽  
J.D. Molkentin ◽  
R.A. Schulz
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Zinc Finger ◽  
Heart Development ◽  
Ectopic Expression ◽  
Cell Formation ◽  
Homeodomain Protein ◽  
Gata Factor ◽  
Cardiac Gene Expression ◽  
Cardiac Gene

The regulation of cardiac gene expression by GATA zinc finger transcription factors is well documented in vertebrates. However, genetic studies in mice have failed to demonstrate a function for these proteins in cardiomyocyte specification. In Drosophila, the existence of a cardiogenic GATA factor has been implicated through the analysis of a cardial cell enhancer of the muscle differentiation gene D-mef2. We show that the GATA gene pannier is expressed in the dorsal mesoderm and required for cardial cell formation while repressing a pericardial cell fate. Ectopic expression of Pannier results in cardial cell overproduction, while co-expression of Pannier and the homeodomain protein Tinman synergistically activate cardiac gene expression and induce cardial cells. The related GATA4 protein of mice likewise functions as a cardiogenic factor in Drosophila, demonstrating an evolutionarily conserved function between Pannier and GATA4 in heart development.

The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity

Development ◽  
2000 ◽  
Vol 127 (23) ◽  
pp. 5191-5201 ◽  
Author(s):  
V. Dubreuil ◽  
M. Hirsch ◽  
A. Pattyn ◽  
J. Brunet ◽  
C. Goridis
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Fate ◽  
Motor Neurons ◽  
Ventricular Zone ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Cell Cycle Exit ◽  
Neuronal Precursors ◽  
Regulation Of Cell Cycle

In the vertebrate neural tube, cell cycle exit of neuronal progenitors is accompanied by the expression of transcription factors that define their generic and sub-type specific properties, but how the regulation of cell cycle withdrawal intersects with that of cell fate determination is poorly understood. Here we show by both loss- and gain-of-function experiments that the neuronal-subtype-specific homeodomain transcription factor Phox2b drives progenitor cells to become post-mitotic. In the absence of Phox2b, post-mitotic neuronal precursors are not generated in proper numbers. Conversely, forced expression of Phox2b in the embryonic chick spinal cord drives ventricular zone progenitors to become post-mitotic neurons and to relocate to the mantle layer. In the neurons thus generated, ectopic expression of Phox2b is sufficient to initiate a programme of motor neuronal differentiation characterised by expression of Islet1 and of the cholinergic transmitter phenotype, in line with our previous results showing that Phox2b is an essential determinant of cranial motor neurons. These results suggest that Phox2b coordinates quantitative and qualitative aspects of neurogenesis, thus ensuring that neurons of the correct phenotype are generated in proper numbers at the appropriate times and locations.

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