scholarly journals p38 (Mapk14/11) occupies a regulatory node governing entry into primitive endoderm differentiation during preimplantation mouse embryo development

Open Biology ◽  
2016 ◽  
Vol 6 (9) ◽  
pp. 160190 ◽  
Author(s):  
Vasanth Thamodaran ◽  
Alexander W. Bruce
Keyword(s):  
Cell Fate ◽  
Embryo Development ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Active Role ◽  
Primitive Endoderm ◽  
Fgf Receptor ◽  
Preimplantation Embryo Development ◽  
Critical Window ◽  
Fate Decision

During mouse preimplantation embryo development, the classically described second cell-fate decision involves the specification and segregation, in blastocyst inner cell mass (ICM), of primitive endoderm (PrE) from pluripotent epiblast (EPI). The active role of fibroblast growth factor (Fgf) signalling during PrE differentiation, particularly in the context of Erk1/2 pathway activation, is well described. However, we report that p38 family mitogen-activated protein kinases (namely p38α/Mapk14 and p38β/Mapk11; referred to as p38-Mapk14/11) also participate in PrE formation. Specifically, functional p38-Mapk14/11 are required, during early-blastocyst maturation, to assist uncommitted ICM cells, expressing both EPI and earlier PrE markers, to fully commit to PrE differentiation. Moreover, functional activation of p38-Mapk14/11 is, as reported for Erk1/2, under the control of Fgf-receptor signalling, plus active Tak1 kinase (involved in non-canonical bone morphogenetic protein (Bmp)-receptor-mediated PrE differentiation). However, we demonstrate that the critical window of p38-Mapk14/11 activation precedes the E3.75 timepoint (defined by the initiation of the classical ‘salt and pepper’ expression pattern of mutually exclusive EPI and PrE markers), whereas appropriate lineage maturation is still achievable when Erk1/2 activity (via Mek1/2 inhibition) is limited to a period after E3.75. We propose that active p38-Mapk14/11 act as enablers, and Erk1/2 as drivers, of PrE differentiation during ICM lineage specification and segregation.

scholarly journals The first cell-fate decision of mouse preimplantation embryo development: integrating cell position and polarity

Open Biology ◽  
2017 ◽  
Vol 7 (11) ◽  
pp. 170210 ◽  
Author(s):  
Aleksandar I. Mihajlović ◽  
Alexander W. Bruce
Keyword(s):  
Cell Fate ◽  
Embryo Development ◽  
Preimplantation Embryo ◽  
Cell Mass ◽  
Cell Fate Decision ◽  
Preimplantation Embryo Development ◽  
Cell Lineages ◽  
Mouse Preimplantation Embryo ◽  
Fate Decision ◽  
Mouse Preimplantation Embryo Development

During the first cell-fate decision of mouse preimplantation embryo development, a population of outer-residing polar cells is segregated from a second population of inner apolar cells to form two distinct cell lineages: the trophectoderm and the inner cell mass (ICM), respectively. Historically, two models have been proposed to explain how the initial differences between these two cell populations originate and ultimately define them as the two stated early blastocyst stage cell lineages. The ‘positional’ model proposes that cells acquire distinct fates based on differences in their relative position within the developing embryo, while the ‘polarity’ model proposes that the differences driving the lineage segregation arise as a consequence of the differential inheritance of factors, which exhibit polarized subcellular localizations, upon asymmetric cell divisions. Although these two models have traditionally been considered separately, a growing body of evidence, collected over recent years, suggests the existence of a large degree of compatibility. Accordingly, the main aim of this review is to summarize the major historical and more contemporarily identified events that define the first cell-fate decision and to place them in the context of both the originally proposed positional and polarity models, thus highlighting their functional complementarity in describing distinct aspects of the developmental programme underpinning the first cell-fate decision in mouse embryogenesis.

scholarly journals DDX21 is a p38-MAPK-sensitive nucleolar protein necessary for mouse preimplantation embryo development and cell-fate specification

Open Biology ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 210092
Author(s):  
Pablo Bora ◽  
Lenka Gahurova ◽  
Andrea Hauserova ◽  
Martina Stiborova ◽  
Rebecca Collier ◽  
...  
Keyword(s):  
Cell Fate ◽  
P38 Mapk ◽  
Embryo Development ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Protein Translation ◽  
Blastocyst Stage ◽  
Translation Regulation ◽  
Cell Stage ◽  
Preimplantation Embryo Development

Successful navigation of the mouse preimplantation stages of development, during which three distinct blastocyst lineages are derived, represents a prerequisite for continued development. We previously identified a role for p38-mitogen-activated kinases (p38-MAPK) regulating blastocyst inner cell mass (ICM) cell fate, specifically primitive endoderm (PrE) differentiation, that is intimately linked to rRNA precursor processing, polysome formation and protein translation regulation. Here, we develop this work by assaying the role of DEAD-box RNA helicase 21 (DDX21), a known regulator of rRNA processing, in the context of p38-MAPK regulation of preimplantation mouse embryo development. We show nuclear DDX21 protein is robustly expressed from the 16-cell stage, becoming exclusively nucleolar during blastocyst maturation, a localization dependent on active p38-MAPK. siRNA-mediated clonal Ddx21 knockdown within developing embryos is associated with profound cell-autonomous and non-autonomous proliferation defects and reduced blastocyst volume, by the equivalent peri-implantation blastocyst stage. Moreover, ICM residing Ddx21 knockdown clones express the EPI marker NANOG but rarely express the PrE differentiation marker GATA4. These data contribute further significance to the emerging importance of lineage-specific translation regulation, as identified for p38-MAPK, during mouse preimplantation development.

scholarly journals DDX21 is a p38-MAPK sensitive nucleolar protein necessary for mouse preimplantation embryo development and cell-fate specification

2021 ◽  
Author(s):  
Pablo Bora ◽  
Lenka Gahurova ◽  
Andrea Hauserova ◽  
Martina Stiborova ◽  
Rebecca Collier ◽  
...  
Keyword(s):  
Cell Fate ◽  
P38 Mapk ◽  
Embryo Development ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Protein Translation ◽  
Blastocyst Stage ◽  
Translation Regulation ◽  
Cell Stage ◽  
Preimplantation Embryo Development

AbstractSuccessful navigation of the mouse preimplantation stages of development, during which three distinct blastocyst lineages are derived, represents a prerequisite for continued development. We previously identified a role for p38-mitogen-activated kinases (p38-MAPK) regulating blastocyst inner cell mass (ICM) cell-fate, specifically primitive endoderm (PrE) differentiation, that is intimately linked to rRNA precursor processing, polysome formation and protein translation regulation. Here, we develop this work by assaying the role of DEAD-box RNA helicase 21 (Ddx21), a known regulator of rRNA processing, in the context of p38-MAPK regulation of preimplantation mouse embryo development. We show nuclear Ddx21 protein is robustly expressed from the 16-cell stage, becoming exclusively nucleolar during blastocyst maturation; a localisation dependent on active p38-MAPK. Efficient siRNA mediated clonal Ddx21 knockdown within developing embryos is associated with profound cell autonomous and non-autonomous proliferation defects and reduced blastocyst volume, by the equivalent peri-implantation blastocyst stage. Moreover, ICM residing Ddx21 knockdown clones express the EPI marker NANOG but rarely express the PrE differentiation marker GATA4. These data contribute extra significance to emerging importance of lineage specific translation regulation, as identified for p38-MAPK, during mouse preimplantation development.

scholarly journals Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Cell Fate Decisions ◽  
Chemical Signalling ◽  
Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

scholarly journals Dynamic changes in Sox2 spatio-temporal expression promote the second cell fate decision through Fgf4/Fgfr2 signaling in preimplantation mouse embryos

2018 ◽  
Vol 475 (6) ◽  
pp. 1075-1089 ◽  
Author(s):  
Tapan Kumar Mistri ◽  
Wibowo Arindrarto ◽  
Wei Ping Ng ◽  
Choayang Wang ◽  
Leng Hiong Lim ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Correlation Spectroscopy ◽  
Binding Interaction ◽  
Regulatory Motifs ◽  
Sox2 Expression ◽  
Spatio Temporal ◽  
Fate Decision

Oct4 and Sox2 regulate the expression of target genes such as Nanog, Fgf4, and Utf1, by binding to their respective regulatory motifs. Their functional cooperation is reflected in their ability to heterodimerize on adjacent cis regulatory motifs, the composite Sox/Oct motif. Given that Oct4 and Sox2 regulate many developmental genes, a quantitative analysis of their synergistic action on different Sox/Oct motifs would yield valuable insights into the mechanisms of early embryonic development. In the present study, we measured binding affinities of Oct4 and Sox2 to different Sox/Oct motifs using fluorescence correlation spectroscopy. We found that the synergistic binding interaction is driven mainly by the level of Sox2 in the case of the Fgf4 Sox/Oct motif. Taking into account Sox2 expression levels fluctuate more than Oct4, our finding provides an explanation on how Sox2 controls the segregation of the epiblast and primitive endoderm populations within the inner cell mass of the developing rodent blastocyst.

scholarly journals Nuclear transfer technique affects mRNA abundance, developmental competence and cell fate of the reconstituted sheep oocytes

Reproduction ◽  
2013 ◽  
Vol 145 (4) ◽  
pp. 345-355 ◽  
Author(s):  
F Moulavi ◽  
S M Hosseini ◽  
M Hajian ◽  
M Forouzanfar ◽  
P Abedi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Embryo Development ◽  
Nuclear Transfer ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Developmental Competence ◽  
Blastocyst Development ◽  
Cleavage Rate ◽  
Nuclear Remodeling

The effect of technical steps of somatic cell nuclear transfer (SCNT) on different aspects of cloned embryo development was investigated in sheep.In vitro-matured oocytes were enucleated in the presence or absence of zona and reconstituted by three different SCNT techniques: conventional zona-intact (ZI-NT), standard zona-free (ZF-NT) and intracytoplasmic nuclear injection (ICI-NT). Stepwise alterations in nuclear remodeling events and in mRNA abundances, throughput and efficiency of cloned embryo development and cell allocation of the resulted blastocysts were assessed. Early signs of nuclear remodeling were observed as soon as 2 h post-reconstitution (hpr) for fusion-based methods of nuclear transfer (ZI-NT and ZF-NT) but were not observable until 4 hpr with the ICI-NT method. The relative mRNA abundances ofHSP90AA1(HSP90),NPM2andATPasegenes were not affected by i) presence or absence of zona, ii) oocyte enucleation method and iii) nuclear transfer method. After reconstitution, however, the relative mRNA contents ofPOU5F1(OCT4) with the ZI-NT and ZF-NT methods and ofPAPOLA(PAP) with ZF-NT were significantly lower than those for the ICI-NT method. Zona removal doubled the throughput of cloned blastocyst development for the ZF-NT technique compared with ZI-NT and ICI-NT. Cleavage rate was not affected by the SCNT protocol, whereas blastocyst yield rate in ICI-NT technique (17.0±1.0%) was significantly (P<0.05; ANOVA) higher than in ZF-NT (7.1±1.5%) but not in the ZI-NT group (11.2±3.3%). Despite the similarities in total cell number, SCNT protocol changed the distribution of cells in the blastocysts, as ZF-NT-cloned blastocysts had significantly smaller inner cell mass than ZI-NT. These results indicate that technical aspects of cloning may result in the variety of cloning phenotypes.

scholarly journals Three-dimensional cell neighbourhood impacts differentiation in the inner mass cells of the mouse blastocyst

2017 ◽  
Author(s):  
Sabine C. Fischer ◽  
Elena Corujo-Simón ◽  
Joaquín Lilao-Garzón ◽  
Ernst H. K. Stelzer ◽  
Silvia Muñoz-Descalzo
Keyword(s):  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Three Dimensional ◽  
Mouse Blastocyst ◽  
Blastocyst Development ◽  
Cell Position ◽  
Fate Decision ◽  
Early Mouse ◽  
Dimensional Cell

AbstractDuring mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterised by the transcription factors NANOG and GATA6, respectively. Here, we present quantitative three-dimensional single cell-based neighbourhood analyses to investigate the spatial distribution of NANOG and GATA6 expression in the ICM of the mouse blastocyst. The cell neighbourhood is characterised by the expression levels of the fate markers in the surrounding cells, together with the number of surrounding cells and cell position. We find that cell neighbourhoods are established in early blastocysts and different for cells expressing different levels of NANOG and GATA6. Highest NANOG expressing cells occupy specific positions within the ICM and are surrounded by 9 neighbours, while GATA6 expressing cells cluster according to their GATA6 levels. The analysis of mutants reveals that NANOG local neighbourhood is regulated by GATA6.Summary statementThree-dimensional cell neighbourhood, which includes fate marker levels, number of neighbouring cells and cell position, determines cell fate decision in early mouse embryos.

scholarly journals Dynamic changes in Sox2 spatio-temporal expression direct the second cell fate decision throughFgf4/Fgfr2signaling in preimplantation mouse embryos

2016 ◽  
Author(s):  
Tapan Kumar Mistri ◽  
Wibowo Arindrarto ◽  
Wei Ping Ng ◽  
Choayang Wang ◽  
Leng Hiong Lim ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Regulatory Elements ◽  
Correlation Spectroscopy ◽  
Binding Interaction ◽  
Preimplantation Mouse ◽  
Spatio Temporal ◽  
Fate Decision

ABSTRACTOct4 and Sox2 regulate the expression of target genes such asNanog, Fgf4andUtf1, by binding to their respective regulatory motifs. Their functional cooperation is reflected in their ability to heterodimerise on adjacentcisregulatory elements, the composite Sox/Oct motif. Given that Oct4 and Sox2 regulate many developmental genes, a quantitative analysis of their synergistic action on different Sox/Oct motifs would yield valuable insights into the mechanisms of early embryonic development. In this study, we measured binding affinities of Oct4 and Sox2 to different Sox/Oct motifs using fluorescence correlation spectroscopy (FCS). We found that the synergistic binding interaction is driven mainly by the level of Sox2 in the case of theFgf4Sox/Oct motif. Taking into accountSox2expression levels fluctuate more thanOct4, our finding provides an explanation on how Sox2 controls the segregation of the epiblast (EPI) and primitive endoderm (PE) populations within the inner cell mass (ICM) of the developing rodent blastocyst.

scholarly journals Cell Fate Clusters in ICM Organoids Arise from Cell Fate Heredity & Division – a Modelling Approach

2019 ◽  
Author(s):  
Tim Liebisch ◽  
Armin Drusko ◽  
Biena Mathew ◽  
Ernst H. K. Stelzer ◽  
Sabine C. Fischer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Lineage ◽  
Cell Fate Decision ◽  
Agent Based ◽  
Cell Fate Decisions ◽  
Fate Decision

ABSTRACTDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first cell fate decision, cells become either part of an outer trophectoderm or part of the inner cell mass. Subsequently, the inner cell mass (ICM) segregates into an embryonic and an extraembryonic lineage, giving rise to the epiblast and the primitive endoderm, respectively. Inner cell mass organoids represent an experimental model system for preimplantation development, mimicking the second cell fate decision taking place in in vivo mouse embryos. In a previous study, the spatial pattern of the different cell lineage types was investigated. The study revealed that cells of the same fate tend to cluster stronger than expected for purely random cell fate decisions. Three major processes are hypothesised to contribute to the final cell fate arrangements at the mid and late blastocysts or 24 h old and 48 h old ICM organoids, respectively: 1) intra- and intercellular chemical signalling; 2) a cell sorting process; 3) cell proliferation. In order to quantify the influence of cell proliferation on the emergence of the observed cell lineage type clustering behaviour, we developed an agent-based model. Hereby, cells are mechanically interacting with direct neighbours, and exert adhesion and repulsion forces. The model was applied to compare several current assumptions of how inner cell mass neighbourhood structures are generated. We tested how different assumptions regarding cell fate switches affect the observed neighbourhood relationships. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. The model further shows that the observed neighbourhood structures can emerge due to cell fate heredity during cell division and allows the inference of a time point for the cell fate decision.STATEMENT OF SIGNIFICANCECell fate decisions in early embryogenesis have been considered random events, causing a random cell fate distribution. Using an agent-based mathematical model, fitted to ICM organoid data, we show that the assumed random distribution of cell fates occurs only for a short time interval, as cell fate heredity and cell division quickly lead to spatial cell fate clustering. Our results show that neighbourhood clustering can emerge without specific neighbourhood interactions affecting the cell fate decision. The approach indicates four consecutive phases of early development: 1) co-expression of cell fate markers, 2) cell fate decision, 3) division and local cell fate clustering, and 4) phase separation, whereby only the phases 1-3 occur in ICM organoids during the first 24h of growth.

scholarly journals Origin of cellular asymmetries in the pre-implantation mouse embryo: a hypothesis

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130536 ◽  
Author(s):  
Katsuyoshi Takaoka ◽  
Hiroshi Hamada
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Cell Fate Decision ◽  
Mouse Development ◽  
Cell Stage ◽  
Stage Embryo ◽  
A Cell ◽  
Fate Decision

The first cell fate decision during mouse development concerns whether a blastomere will contribute to the inner cell mass (ICM; which gives rise to the embryo proper) or to trophectoderm (TE; which gives rise to the placenta). The position of a cell within an 8- to 16-cell-stage embryo correlates with its future fate, with outer cells contributing to TE and inner cells to the ICM. It remains unknown, however, whether an earlier pre-pattern exists. Here, we propose a hypothesis that could account for generation of such a pre-pattern and which is based on epigenetic asymmetry (such as in histone or DNA methylation) between maternal and paternal genomes in the zygote.

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