Suppression of GATA factor activity causes axis duplication in Xenopus

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4595-4605 ◽  
Author(s):  
T.G. Sykes ◽  
A.R. Rodaway ◽  
M.E. Walmsley ◽  
R.K. Patient
Keyword(s):  
Cell Fate ◽  
Homeobox Gene ◽  
Dominant Negative ◽  
Gata Factor ◽  
Dorsoventral Axis ◽  
Morphogenetic Protein ◽  
Head Formation ◽  
Bmp Signalling ◽  
Bmp Antagonist

In Xenopus, the dorsoventral axis is patterned by the interplay between active signalling in ventral territories, and secreted antagonists from Spemann's organiser. Two signals are important in ventral cells, bone morphogenetic protein-4 (BMP-4) and Wnt-8. BMP-4 plays a conserved role in patterning the vertebrate dorsoventral axis, whilst the precise role of Wnt-8 and its relationship with BMP-4, are still unclear. Here we have investigated the role played by the GATA family of transcription factors, which are expressed in ventral mesendoderm during gastrulation and are required for the differentiation of blood and endodermal tissues. Injection ventrally of a dominant-interfering GATA factor (called G2en) induced the formation of secondary axes that phenocopy those induced by the dominant-negative BMP receptor. However, unlike inhibiting BMP signalling, inhibiting GATA activity in the ectoderm does not lead to neuralisation. In addition, analysis of gene expression in G2en injected embryos reveals that at least one known target gene for BMP-4, the homeobox gene Vent-2, is unaffected. In contrast, the expression of Wnt-8 and the homeobox gene Vent-1 is suppressed by G2en, whilst the organiser-secreted BMP antagonist chordin becomes ectopically expressed. These data therefore suggest that GATA activity is essential for ventral cell fate and that subsets of ventralising and dorsalising genes require GATA activity for their expression and suppression, respectively. Finally, using G2en, we show that suppression of Wnt-8 expression, in conjunction with blocked BMP signalling, does not lead to head formation, suggesting that the head-suppressing Wnt signal may not be Wnt-8.

scholarly journals Active repression by unliganded retinoid receptors in development

2003 ◽  
Vol 161 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Andrea D. Weston ◽  
Bruce Blumberg ◽  
T. Michael Underhill
Keyword(s):  
Retinoic Acid ◽  
Cell Fate ◽  
Thyroid Hormone Receptor ◽  
Trichostatin A ◽  
Skeletal Development ◽  
Dominant Negative ◽  
Retinoid Receptors ◽  
Head Formation ◽  
Developmental Role

The retinoid receptors have major roles throughout development, even in the absence of ligand. Here, we summarize an emerging theme whereby gene repression, mediated by unliganded retinoid receptors, can dictate cell fate. In addition to activating transcription, retinoid receptors actively repress gene transcription by recruiting cofactors that promote chromatin compaction. Two developmental processes for which gene silencing by the retinoid receptors is essential are head formation in Xenopus and skeletal development in the mouse. Inappropriate repression, by oncogenic retinoic acid (RA)**Abbreviations used in this paper: APL, acute promyelocytic leukemia; dnRARα, dominant–negative version of the RARα; E, embryonic age; HDAC, histone deacetylase; LCoR, ligand-dependent corepressor; NCoR, nuclear receptor corepressor; RA, retinoic acid; RAR, RA receptor; RARE, RXR homodimer bound to bipartite response element; RXR, retinoid X receptor; TSA, trichostatin A; CYP26, cytochrome p450, 26; TR, thyroid hormone receptor. receptor (RAR) fusion proteins, blocks myeloid differentiation leading to a rare form of leukemia. Our current understanding of the developmental role of retinoid repression and future perspectives in this field are discussed.

scholarly journals A Genome-Wide RNA Interference Screen Identifies a Differential Role of the Mediator CDK8 Module Subunits for GATA/ RUNX-Activated Transcription in Drosophila

2010 ◽  
Vol 30 (11) ◽  
pp. 2837-2848 ◽  
Author(s):  
Vanessa Gobert ◽  
Dani Osman ◽  
Stéphanie Bras ◽  
Benoit Augé ◽  
Muriel Boube ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Interference ◽  
Cell Fate ◽  
Gata Factor ◽  
Hematopoietic System ◽  
Crystal Cell ◽  
Genome Wide ◽  
A Genome

ABSTRACT Transcription factors of the RUNX and GATA families play key roles in the control of cell fate choice and differentiation, notably in the hematopoietic system. During Drosophila hematopoiesis, the RUNX factor Lozenge and the GATA factor Serpent cooperate to induce crystal cell differentiation. We used Serpent/Lozenge-activated transcription as a paradigm to identify modulators of GATA/RUNX activity by a genome-wide RNA interference screen in cultured Drosophila blood cells. Among the 129 factors identified, several belong to the Mediator complex. Mediator is organized in three modules plus a regulatory “CDK8 module,” composed of Med12, Med13, CycC, and Cdk8, which has long been thought to behave as a single functional entity. Interestingly, our data demonstrate that Med12 and Med13 but not CycC or Cdk8 are essential for Serpent/Lozenge-induced transactivation in cell culture. Furthermore, our in vivo analysis of crystal cell development show that, while the four CDK8 module subunits control the emergence and the proliferation of this lineage, only Med12 and Med13 regulate its differentiation. We thus propose that Med12/Med13 acts as a coactivator for Serpent/Lozenge during crystal cell differentiation independently of CycC/Cdk8. More generally, we suggest that the set of conserved factors identified herein may regulate GATA/RUNX activity in mammals.

A role for the vegetally expressed Xenopus gene Mix.1 in endoderm formation and in the restriction of mesoderm to the marginal zone

Development ◽  
1998 ◽  
Vol 125 (13) ◽  
pp. 2371-2380 ◽  
Author(s):  
P. Lemaire ◽  
S. Darras ◽  
D. Caillol ◽  
L. Kodjabachian
Keyword(s):  
Marginal Zone ◽  
Ectopic Expression ◽  
Homeobox Gene ◽  
Early Response ◽  
Endoderm Differentiation ◽  
Head Formation ◽  
Mutual Repression ◽  
Regulatory Loop ◽  
Strong Activator

We have studied the role of the activin immediate-early response gene Mix.1 in mesoderm and endoderm formation. In early gastrulae, Mix.1 is expressed throughout the vegetal hemisphere, including marginal-zone cells expressing the trunk mesodermal marker Xbra. During gastrulation, the expression domains of Xbra and Mix.1 become progressively exclusive as a result of the establishment of a negative regulatory loop between these two genes. This mutual repression is important for the specification of the embryonic body plan as ectopic expression of Mix.1 in the Xbra domain suppresses mesoderm differentiation. The same effect was obtained by overexpressing VP16Mix.1, a fusion protein comprising the strong activator domain of viral VP16 and the homeodomain of Mix.1, suggesting that Mix.1 acts as a transcriptional activator. Mix.1 also has a role in endoderm formation. It cooperates with the dorsal vegetal homeobox gene Siamois to activate the endodermal markers edd, Xlhbox8 and cerberus in animal caps. Conversely, vegetal overexpression of enRMix.1, an antimorphic Mix.1 mutant, leads to a loss of endoderm differentiation. Finally, by targeting enRMix.1 expression to the anterior endoderm, we could test the role of this tissue during embryogenesis and show that it is required for head formation.

scholarly journals Single nucleotide polymorphism of bone morphogenetic protein 4 gene: A risk factor of non-syndromic cleft lip with or without palate

2015 ◽  
Vol 48 (02) ◽  
pp. 159-164 ◽  
Author(s):  
Sathyaprasad Savitha ◽  
S. M. Sharma ◽  
Shetty Veena ◽  
R. Rekha
Keyword(s):  
Bone Morphogenetic Protein ◽  
Cleft Lip ◽  
Paediatric Population ◽  
Single Nucleotide ◽  
Morphogenetic Protein ◽  
Increased Risk ◽  
Polymerase Chain ◽  
Bmp Signalling ◽  
Control Study

ABSTRACT Background: The bone morphogenetic protein (BMP) signalling pathway is crucial in a number of developmental processes and is critical in the formation of variety of craniofacial elements including cranial neural crest, facial primordium, tooth, lip and palate. It is an important mediator in regulation of lip and palate fusion, cartilage and bone formation. Aim: To study the role of mutation of BMP4 genes in the aetiology of non-syndromic cleft lip with or without palate (NSCL ± P) and identify it directly from human analyses. Materials and Methods: A case-control study was done to evaluate whether BMP4T538C polymorphism, resulting in an amino acid change of Val=Ala (V152A) in the polypeptide, is associated with NSCL ± P in an Indian paediatric population. Genotypes of 100 patients with NSCL ± P and 100 controls (in whom absence of CL ± P was confirmed in three generations) were detected using a polymerase chain reaction-restriction fragment length polymorphism strategy. Logistic regression was performed to evaluate allele and genotype association with NSCLP. Results: Results showed significant association between homozygous CC genotype with CL ± P (odds ratio [OR]-5.59 and 95% confidence interval [CI] = 2.85-10.99). The 538C allele carriers showed an increased risk of NSCL ± P as compared with 538 T allele (OR - 4.2% CI = 2.75-6.41). Conclusion: This study suggests an association between SNP of BMP4 gene among carriers of the C allele and increased risk for NSCLP in an Indian Population. Further studies on this aspect can scale large heights in preventive strategies for NSCLP that may soon become a reality.

scholarly journals The role of the Rx homeobox gene in retinal progenitor proliferation and cell fate specification

2018 ◽  
Vol 151 ◽  
pp. 18-29 ◽  
Author(s):  
H.M. Rodgers ◽  
V.J. Huffman ◽  
V.A. Voronina ◽  
M. Lewandoski ◽  
P.H. Mathers
Keyword(s):  
Cell Fate ◽  
Homeobox Gene ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Retinal Progenitor

The endocytic adaptor Numb regulates thymus size by modulating pre-TCR signaling during asymmetric division

Blood ◽  
2010 ◽  
Vol 116 (10) ◽  
pp. 1705-1714 ◽  
Author(s):  
Rocio Aguado ◽  
Nadia Martin-Blanco ◽  
Michael Caraballo ◽  
Matilde Canelles
Keyword(s):  
Cell Fate ◽  
Asymmetric Division ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Daughter Cells ◽  
Fate Determinants ◽  
Cell Fate Determinants

Abstract Stem cells must proliferate and differentiate to generate the lineages that shape mature organs; understanding these 2 processes and their interaction is one of the central themes in current biomedicine. An intriguing aspect is asymmetric division, by which 2 daughter cells with different fates are generated. Several cell fate determinants participate in asymmetric division, with the endocytic adaptor Numb as the best-known example. Here, we have explored the role of asymmetric division in thymocyte development, visualizing the differential segregation of Numb and pre-TCR in thymic precursors. Analysis of mice where Numb had been inhibited by expressing a dominant negative revealed enhanced pre–T-cell receptor (TCR) signaling and a smaller thymus. Conversely, Numb overexpression resulted in loss of asymmetric division and a larger thymus. The conclusion is that Numb determines the levels of pre-TCR signaling in dividing thymocytes and, ultimately, the size of the pool from which mature T lymphocytes are selected.

scholarly journals Abnormalities of the Genitourinary Tract in Female Mice Lacking GATA5

2000 ◽  
Vol 20 (14) ◽  
pp. 5256-5260 ◽  
Author(s):  
Jeffery D. Molkentin ◽  
Kevin M. Tymitz ◽  
James A. Richardson ◽  
Eric N. Olson
Keyword(s):  
Cell Fate ◽  
Null Allele ◽  
Cell Fate Specification ◽  
Mammalian Development ◽  
Gata Factor ◽  
Genitourinary System ◽  
Gata Factors ◽  
Developing Heart

ABSTRACT Members of the GATA family of transcription factors play important roles in cell fate specification, differentiation, and morphogenesis during mammalian development. GATA5, the only one of the six vertebrate GATA factor genes not yet inactivated in mice, is expressed in a pattern that overlaps with but is distinct from that of other GATA factor genes. During mouse embryogenesis, GATA5 is expressed first in the developing heart and subsequently in the lung, vasculature, and genitourinary system. To investigate the function of GATA5 in vivo, we created mice homozygous for a GATA5 null allele. Homozygous mutants were viable and fertile, but females exhibited pronounced genitourinary abnormalities that included vaginal and uterine defects and hypospadias. In contrast, the genitourinary system was unaffected in male GATA5 mutants. These results reveal a specific role of GATA5 in development of the female genitourinary system and suggest that other GATA factors may have functions overlapping those of GATA5 in other tissues.

Role of Goosecoid, Xnot and Wnt antagonists in the maintenance of the notochord genetic programme in Xenopus gastrulae

Development ◽  
2001 ◽  
Vol 128 (19) ◽  
pp. 3783-3793 ◽  
Author(s):  
Hitoyoshi Yasuo ◽  
Patrick Lemaire
Keyword(s):  
Bone Morphogenetic Protein ◽  
Neural Tube ◽  
Wnt Pathway ◽  
Transcriptional Repressor ◽  
Ventral Side ◽  
Morphogenetic Protein ◽  
Bmp Signalling ◽  
Genetic Programme ◽  
Shed Light

The Xenopus trunk organiser recruits neighbouring tissues into secondary trunk axial and paraxial structures and itself differentiates into notochord. The inductive properties of the trunk organiser are thought to be mediated by the secretion of bone morphogenetic protein (BMP) antagonists. Ectopic repression of BMP signals on the ventral side is sufficient to mimic the inductive properties of the trunk organiser. Resultant secondary trunks contain somite and neural tube, but no notochord. We show that inhibition of BMP signalling is sufficient for the initiation of the trunk organiser genetic programme at the onset of gastrulation. During late gastrulation, however, this programme is lost, due to an invasion of secreted Wnts from neighbouring tissues. Maintenance of this programme requires co-repression of BMP and Wnt signalling within the presumptive notochord region. To shed light on the molecular cascade that leads to the repression of the Wnt pathway, we looked for individual organiser genes whose overexpression could complement the inhibition of BMP signalling to promote notochord formation in the secondary trunks. Two genes, gsc and Xnot, were thus identified and shown to act in different ways. Xnot acts as a transcriptional repressor within the mesodermal region. Gsc acts in deeper vegetal cells, where it regulates Frzb expression to maintain Xnot expression in the neighbouring notochord territory. These results suggest that, during gastrulation, the necessary repression of Wnt/β-catenin signalling in notochord precursors is achieved by the action of secreted inhibitors, such as Frzb, emitted by gsc-expressing dorsal vegetal cells.

scholarly journals GATA-4 Regulates Bcl-2 Expression in Ovarian Granulosa Cell Tumors

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5635-5642 ◽  
Author(s):  
Antti Kyrönlahti ◽  
Maarit Rämö ◽  
Maija Tamminen ◽  
Leila Unkila-Kallio ◽  
Ralf Butzow ◽  
...  
Keyword(s):  
Cell Fate ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Dominant Negative ◽  
Rt Pcr ◽  
Cyclin D2 ◽  
Granulosa Cell Tumors ◽  
Ovarian Granulosa Cell ◽  
Cell Cycle Regulator Cyclin

Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the antiapoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2, and cyclin D2, and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2, and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays, and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression up-regulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2.

EGF receptor attenuates Dpp signaling and helps to distinguish the wing and leg cell fates in Drosophila

Development ◽  
2000 ◽  
Vol 127 (17) ◽  
pp. 3769-3776 ◽  
Author(s):  
K. Kubota ◽  
S. Goto ◽  
K. Eto ◽  
S. Hayashi
Keyword(s):  
Spatial Distribution ◽  
Cell Fate ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Homeobox Gene ◽  
Cell Fate Decision ◽  
Cell Fates ◽  
Dorsoventral Axis ◽  
Fate Decision ◽  
Number Of Cells

Wing and leg precursors of Drosophila are recruited from a common pool of ectodermal cells expressing the homeobox gene Dll. Induction by Dpp promotes this cell fate decision toward the wing and proximal leg. We report here that the receptor tyrosine kinase EGFR antagonizes the wing-promoting function of Dpp and allows recruitment of leg precursor cells from uncommitted ectodermal cells. By monitoring the spatial distribution of cells responding to Dpp and EGFR, we show that nuclear transduction of the two signals peaks at different position along the dorsoventral axis when the fates of wing and leg discs are specified and that the balance of the two signals assessed within the nucleus determines the number of cells recruited to the wing. Differential activation of the two signals and the cross talk between them critically affect this cell fate choice.

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