The Polycomb-group gene eed is required for normal morphogenetic movements during gastrulation in the mouse embryo

Development ◽  
1998 ◽  
Vol 125 (22) ◽  
pp. 4495-4506 ◽  
Author(s):  
C. Faust ◽  
K.A. Lawson ◽  
N.J. Schork ◽  
B. Thiel ◽  
T. Magnuson
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Transcriptional Repression ◽  
Positional Cloning ◽  
Primitive Streak ◽  
Polycomb Group ◽  
Substantial Contribution ◽  
Loss Of Function ◽  
Morphogenetic Movements ◽  
Extraembryonic Mesoderm

We have characterized an induced mutation, called embryonic ectoderm development or eed, that disrupts A-P patterning of the mouse embryo during gastrulation. Positional cloning of this gene revealed it to be the highly conserved homologue of the Drosophila gene extra sex combs, which is required for maintenance of long-term transcriptional repression of homeotic gene expression. Mouse embryos homozygous for loss-of-function alleles of eed initiate gastrulation but display abnormal mesoderm production. Very little embryonic mesoderm is produced; in contrast, extraembryonic mesoderm is relatively abundant. These observations, along with mRNA in situ hybridization analyses, suggested a defect in the anterior primitive streak, from which much of the embryonic mesoderm of the wild-type embryo is derived. To analyse this defect, we initiated clonal analysis of the pre-streak epiblast in eed mutant embryos, using the lineage tracer horseradish peroxidase (HRP). The results of these studies indicate that epiblast cells ingress through the anterior streak, but the newly formed mesoderm does not migrate anteriorly and is mislocalized to the extraembryonic compartment. Abnormal localization of mesoderm to the extraembryonic region did not appear to be due to a restriction and alteration of distal epiblast cell fate, since the majority of clones produced from regions fated to ingress through the anterior streak were mixed, displaying descendants in both embryonic and extraembryonic derivatives. eed mutant embryos also fail to display proper epiblast expansion, particularly with respect to the A-P axis. Based on patterns of clonal spread and calculated clone doubling times for the epiblast, this does not appear to be due to decreased epiblast growth. Rather, epiblast, which is normally fated to make a substantial contribution to the axial midline, appears to make mesoderm preferentially. The data are discussed in terms of global morphogenetic movements in the mouse gastrula and a disruption of signalling activity in the anterior primitive streak.

scholarly journals Zebrafish Polycomb repressive complex-2 critical roles are largely Ezh2- over Ezh1-driven and concentrate during early embryogenesis

2021 ◽  
Author(s):  
Gabriel A. Yette ◽  
Scott Stewart ◽  
Kryn Stankunas
Keyword(s):  
Cell Fate ◽  
Transcriptional Repression ◽  
Axial Skeleton ◽  
Early Embryogenesis ◽  
Loss Of Function ◽  
Allelic Series ◽  
Polycomb Repressive Complex ◽  
Genetic Studies ◽  
Polycomb Repressive Complex 2 ◽  
Early Developmental

ABSTRACTPolycomb repressive complex-2 (PRC2) methylation of histone H3 lysine-27 (H3K27me) is associated with stable transcriptional repression. PRC2 famously silences Hox genes to maintain anterior-posterior segment identities but also enables early cell fate specification, restrains progenitor cell differentiation, and canalizes cell identities. Zebrafish PRC2 genetic studies have focused on ezh2, which, with its paralog ezh1, encodes the H3K27 methyltransferase component. ezh2 loss-of-function mutants reinforce essential vertebrate PRC2 functions during early embryogenesis albeit with limited contributions to body plan establishment. However, redundancy with ezh1 and the lethality of maternal-zygotic homozygous ezh2 nulls could obscure additional early developmental and organogenesis roles of PRC2. Here, we combine new and existing zebrafish ezh1 and ezh2 alleles to show collective maternal/zygotic ezh2 exclusively provides earliest embryonic PRC2 H3K27me3 activity. Zygotic ezh1, which becomes progressively expressed as ezh2 levels dissipate, has minor redundant and noncompensatory larval roles but itself is not required for viability or fertility. Zygotic Ezh2/PRC2 promotes correct craniofacial bone shape and size by maintaining proliferative pre-osteoblast pools. An ezh2 allelic series including disrupted maternal ezh2 uncovers axial skeleton homeotic transformations and pleiotropic organogenesis defects. Further, once past a critical early window, we show zebrafish can develop near normally with minimal bulk H3K27me3. Our results suggest Ezh2-containing PRC2 stabilizes rather than instructs early developmental decisions while broadly contributing to organ size and embellishment.

scholarly journals Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferation in vivo

2019 ◽  
Author(s):  
Aniek van der Vaart ◽  
Molly Godfrey ◽  
Vincent Portegijs ◽  
Sander van den Heuvel
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Repression ◽  
Human Cancer ◽  
Gene Knockout ◽  
Selective Advantage ◽  
Polycomb Group ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Suppressor Activity

AbstractSWI/SNF complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb-group (PcG) proteins. Genes that encode SWI/SNF subunits are frequently mutated in human cancer. The selective advantage, subunit bias, and common heterozygosity of such mutations remains poorly understood. Here, we characterized how functional loss of various SWI/SNF subunits and PcG EZH2 affect proliferation-differentiation decisions in vivo, making use of the reproducible development of the nematode C. elegans. We applied a lineage-specific genetics strategy to create partial or complete SWI/SNF subunit loss, as well as double gene knockout with PcG EZH2. Our data show that a high SWI/SNF BAF dosage is needed to oppose Polycomb-mediated transcriptional repression and to arrest cell division during differentiation. In contrast, even in the absence of the PcG EZH2-related methyltransferase, a low level of the SWI/SNF BAF complex is necessary and sufficient to sustain cell proliferation and hyperplasia. Our data provide experimental support for the theory that during carcinogenesis partial SWI/SNF BAF loss-of-function mutations are selected because they eliminate a tumor suppressor activity while maintaining an essential transcription regulatory function.

The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation

Development ◽  
1997 ◽  
Vol 124 (9) ◽  
pp. 1631-1642 ◽  
Author(s):  
P.P. Tam ◽  
M. Parameswaran ◽  
S.J. Kinder ◽  
R.P. Weinberger
Keyword(s):  
Cell Fate ◽  
Primitive Streak ◽  
Heart Cells ◽  
Lateral Plate Mesoderm ◽  
Lateral Plate ◽  
Tissue Movement ◽  
Heart Field ◽  
Morphogenetic Event ◽  
Extraembryonic Mesoderm

The cardiogenic potency of cells in the epiblast of the early primitive-streak stage (early PS) embryo was tested by heterotopic transplantation. The results of this study show that cells in the anterior and posterior epiblast of the early PS-stage embryos have similar cardiogenic potency, and that they differentiated to heart cells after they were transplanted directly to the heart field of the late PS embryo. That the epiblast cells can acquire a cardiac fate without any prior act of ingression through the primitive streak or movement within the mesoderm suggests that neither morphogenetic event is critical for the specification of the cardiogenic fate. The mesodermal cells that have recently ingressed through the primitive streak can express a broad cell fate that is characteristic of the pre-ingressed cells in the host when they were returned to the epiblast. However, mesoderm cells that have ingressed through the primitive streak did not contribute to the lateral plate mesoderm after transplantation back to the epiblast, implying that some restriction of lineage potency may have occurred during ingression. Early PS stage epiblast cells that were transplanted to the epiblast of the mid PS host embryos colonised the embryonic mesoderm but not the extraembryonic mesoderm. This departure from the normal cell fate indicates that the allocation of epiblast cells to the mesodermal lineages is dependent on the timing of their recruitment to the primitive streak and the morphogenetic options that are available to the ingressing cells at that instance.

The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4691-4701 ◽  
Author(s):  
S.J. Kinder ◽  
T.E. Tsang ◽  
G.A. Quinlan ◽  
A.K. Hadjantonakis ◽  
A. Nagy ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Mouse Embryo ◽  
Primitive Streak ◽  
Yolk Sac ◽  
Cell Lineages ◽  
Anteroposterior Axis ◽  
Extraembryonic Mesoderm ◽  
Extraembryonic Membranes ◽  
Lateral Mesoderm ◽  
Late Stages

The prospective fate of cells in the primitive streak was examined at early, mid and late stages of mouse gastrula development to determine the order of allocation of primitive streak cells to the mesoderm of the extraembryonic membranes and to the fetal tissues. At the early-streak stage, primitive streak cells contribute predominantly to tissues of the extraembryonic mesoderm as previously found. However, a surprising observation is that the erythropoietic precursors of the yolk sac emerge earlier than the bulk of the vitelline endothelium, which is formed continuously throughout gastrula development. This may suggest that the erythropoietic and the endothelial cell lineages may arise independently of one another. Furthermore, the extraembryonic mesoderm that is localized to the anterior and chorionic side of the yolk sac is recruited ahead of that destined for the posterior and amnionic side. For the mesodermal derivatives in the embryo, those destined for the rostral structures such as heart and forebrain mesoderm ingress through the primitive streak early during a narrow window of development. They are then followed by those for the rest of the cranial mesoderm and lastly the paraxial and lateral mesoderm of the trunk. Results of this study, which represent snapshots of the types of precursor cells in the primitive streak, have provided a better delineation of the timing of allocation of the various mesodermal lineages to specific compartments in the extraembryonic membranes and different locations in the embryonic anteroposterior axis.

The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis

Development ◽  
1987 ◽  
Vol 99 (1) ◽  
pp. 109-126 ◽  
Author(s):  
P.P. Tam ◽  
R.S. Beddington
Keyword(s):  
Anterior Part ◽  
Primitive Streak ◽  
Paraxial Mesoderm ◽  
Substantial Contribution ◽  
Fate Map ◽  
Extraembryonic Mesoderm ◽  
Lateral Mesoderm ◽  
Embryonic Ectoderm ◽  
Specific Labelling

Orthotopic grafts of [3H]thymidine-labelled cells have been used to demonstrate differences in the normal fate of tissue located adjacent to and in different regions of the primitive streak of 8th day mouse embryos developing in vitro. The posterior streak produces predominantly extraembryonic mesoderm, while the middle portion gives rise to lateral mesoderm and the anterior region generates mostly paraxial mesoderm, gut and notochord. Embryonic ectoderm adjacent to the anterior part of the streak contributes mainly to paraxial mesoderm and neurectoderm. This pattern of colonization is similar to the fate map constructed in primitive-streak-stage chick embryos. Similar grafts between early-somite-stage (9th day) embryos have established that the older primitive streak continues to generate embryonic mesoderm and endoderm, but ceases to make a substantial contribution to extraembryonic mesoderm. Orthotopic grafts and specific labelling of ectodermal cells with wheat germ agglutinin conjugated to colloidal gold (WGA-Au) have been used to analyse the recruitment of cells into the paraxial mesoderm of 8th and 9th day embryos. The continuous addition of primitive-streak-derived cells to the paraxial mesoderm is confirmed and the distribution of labelled cells along the craniocaudal sequence of somites is consistent with some cell mixing occurring within the presomitic mesoderm.

scholarly journals Human Papillomavirus Type 16 E7 Oncoprotein Associates with E2F6

2008 ◽  
Vol 82 (17) ◽  
pp. 8695-8705 ◽  
Author(s):  
Margaret E. McLaughlin-Drubin ◽  
Kyung-Won Huh ◽  
Karl Münger
Keyword(s):  
Human Papillomavirus ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Defense Mechanism ◽  
Simian Virus 40 ◽  
T Antigen ◽  
S Phase ◽  
Polycomb Group ◽  
Keratinocyte Differentiation ◽  
Hpv E7

ABSTRACT The papillomavirus life cycle is intimately coupled to the differentiation state of the infected epithelium. Since papillomaviruses lack most of the rate-limiting enzymes required for genome synthesis, they need to uncouple keratinocyte differentiation from cell cycle arrest and maintain or reestablish a replication-competent state within terminally differentiated keratinocytes. The human papillomavirus (HPV) E7 protein appears to be a major determinant for this activity and induces aberrant S-phase entry through the inactivation of the retinoblastoma tumor suppressor and related pocket proteins. In addition, E7 can abrogate p21 and p27. Together, this leads to the activation of E2F1 to E2F5, enhanced expression of E2F-responsive genes, and increased cdk2 activity. E2F6 is a pRB-independent, noncanonical member of the E2F transcription factor family that acts as a transcriptional repressor. E2F6 expression is activated in S phase through an E2F-dependent mechanism and thus may provide a negative-feedback mechanism that slows down S-phase progression and/or exit in response to the activation of the other E2F transcription factors. Here, we show that low- and high-risk HPV E7 proteins, as well as simian virus 40 T antigen and adenovirus E1A, can associate with and inactivate the transcriptional repression activity of E2F6, thereby subverting a critical cellular defense mechanism. This may result in the extended S-phase competence of HPV-infected cells. E2F6 is a component of polycomb group complexes, which bind to silenced chromatin and are critical for the maintenance of cell fate. We show that E7-expressing cells show decreased staining for E2F6/polycomb complexes and that this is at least in part dependent on the association with E2F6.

scholarly journals TheTrithorax-mimicAllele ofEnhancer of zesteRenders Active Domains of Target Genes Accessible toPolycomb-Group-Dependent Silencing inDrosophila melanogaster

Genetics ◽  
2001 ◽  
Vol 159 (3) ◽  
pp. 1135-1150 ◽  
Author(s):  
Izabella Bajusz ◽  
László Sipos ◽  
Zoltán Györgypál ◽  
Elizabeth A Carrington ◽  
Richard S Jones ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Target Genes ◽  
Critical Role ◽  
Polycomb Group ◽  
Single Amino Acid ◽  
Homeotic Genes ◽  
Loss Of Function ◽  
Chromatin Domains ◽  
Trithorax Group ◽  
Inactive Chromatin

AbstractTwo antagonistic groups of genes, the trithorax- and the Polycomb-group, are proposed to maintain the appropriate active or inactive state of homeotic genes set up earlier by transiently expressed segmentation genes. Although some details about the mechanism of maintenance are available, it is still unclear how the initially active or inactive chromatin domains are recognized by either the trithorax-group or the Polycomb-group proteins. We describe an unusual dominant allele of a Polycomb-group gene, Enhancer of zeste, which mimics the phenotype of loss-of-function mutations in trithorax-group genes. This mutation, named E(z)Trithorax mimic [E(z)Trm], contains a single-amino-acid substitution in the conserved SET domain. The strong dominant trithorax-like phenotypes elicited by this E(z) allele suggest that the mutated arginine-741 plays a critical role in distinguishing between active and inactive chromatin domains of the homeotic gene complexes. We have examined the modification of E(z)Trm phenotypes by mutant alleles of PcG and trxG genes and other mutations that alter the phosphorylation of nuclear proteins, covalent modifications of histones, or histone dosage. These data implicate some trxG genes in transcriptional repression as well as activation and provide genetic evidence for involvement of histone modifications in PcG/trxG-dependent transcriptional regulation.

scholarly journals Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 147 (4) ◽  
pp. 1675-1695 ◽  
Author(s):  
Frans E Tax ◽  
James H Thomas ◽  
Edwin L Ferguson ◽  
H Robert Horvitzt
Keyword(s):  
Cell Fate ◽  
Low Frequency ◽  
Signal Transduction Pathway ◽  
Temperature Shift ◽  
Egg Laying ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Suppressor Mutations

Abstract We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-l7, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup1 7 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

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