The Florey Lecture, 1988 - From egg to embryo: the initiation of cell differentiation in Amphibia

1989 ◽  
Vol 237 (1286) ◽  
pp. 11-25 ◽  
Keyword(s):  
Muscle Cell ◽  
Gene Activation ◽  
Cell Formation ◽  
Gene Promoter ◽  
Cell Types ◽  
Specific Gene ◽  
Embryonic Induction ◽  
Differentiated Cells ◽  
Wide Range ◽  
Muscle Genes

Some of the principles by which different cell types first arise at the beginning of animal development are illustrated by muscle cell formation in Amphibia. If the nucleus of a differentiated muscle cell is transplanted to an enucleated egg, some of the resulting embryos develop into tadpoles with a wide range of normally differentiated cells. These experiments show that genes undergo major changes in activity as a response to components of egg cytoplasm. Two fundamental mechanisms account for the regional activation of genes in early embryos. One involves the effect of localized ‘determinants’ in egg cytoplasm, and the other concerns cell interactions or embryonic induction. Both these mechanisms seem to be responsible for muscle cell formation in amphibian development. The old problem of embryonic induction has recently become accessible to analysis at the molecular level, especially in the case of the mesoderm or muscle-forming induction. This has been greatly facilitated by using a sensitive and quantitative assay to detect the first transcripts of muscle genes a few hours after the start of induction. The role of early events and of interactions among like cells during response to induction is discussed. In analysing specific gene activation following induction, DNA injection into fertilized eggs has shown that a very small part of the cardiac actin gene promoter is sufficient to enable it to respond to induction. Although the experimental work summarized here has been done on amphibian embryos, which are more suitable than other embryos for embryological manipulation, the conclusions reached are believed to be generally applicable to the development of other organisms.

Non-autonomous regulation of a graded, PKA-mediated transcriptional activation signal for cell patterning

Development ◽  
1998 ◽  
Vol 125 (20) ◽  
pp. 3947-3954
Author(s):  
P. Balint-Kurti ◽  
G.T. Ginsburg ◽  
J. Liu ◽  
A.R. Kimmel
Keyword(s):  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Gene Activation ◽  
Distal Segment ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Specific Gene ◽  
Differentiated Cells ◽  
Extracellular Signal ◽  
Dependent Protein

The pseudoplasmodium or migrating slug of Dictyostelium is composed of non-terminally differentiated cells, organized along an anteroposterior axis. Cells in the anterior region of the slug define the prestalk compartment, whereas most of the posterior zone consists of prespore cells. We now present evidence that the cAMP-dependent protein kinase (PKA) and the RING domain/leucine zipper protein rZIP interact genetically to mediate a transcriptional activation gradient that regulates the differentiation of prespore cells within the posterior compartment of the slug. PKA is absolutely required for prespore differentiation. In contrast, rZIP negatively regulates prespore patterning; rzpA- cells, which lack rZIP, have reduced prestalk differentiation and a corresponding increase in prespore-specific gene expression. Using cell-specific markers and chimaeras of wild-type and rzpA- cells, we show that rZIP functions non-autonomously to establish a graded, prespore gene activation signal but autonomously to localize prespore expression. Overexpression of either the catalytic subunit or a dominant-negative regulatory subunit of PKA further demonstrates that PKA lies within the intracellular pathway that mediates the extracellular signal and regulates prespore patterning. Finally, we show that a 5′-distal segment within a prespore promoter that is responsive to a graded signal is also sensitive to PKA and rZIP, indicating that it acts directly at the level of prespore-specific gene transcription for regulation.

scholarly journals Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Natalie M. Clark ◽  
Eli Buckner ◽  
Adam P. Fisher ◽  
Emily C. Nelson ◽  
Thomas T. Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Gene Networks ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Renewal ◽  
Cell Type ◽  
Stem Cell Maintenance ◽  
Differentiated Cells ◽  
Cell Type Specific ◽  
Stem Cell Type

AbstractStem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred to here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allows us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

scholarly journals MAGI-1 interacts with Slo1 channel proteins and suppresses Slo1 expression on the cell surface

2009 ◽  
Vol 297 (1) ◽  
pp. C55-C65 ◽  
Author(s):  
Lon D. Ridgway ◽  
Eun Young Kim ◽  
Stuart E. Dryer
Keyword(s):  
Cell Surface ◽  
Outward Current ◽  
Cell Types ◽  
Surface Expression ◽  
Scaffolding Protein ◽  
Actin Binding ◽  
Differentiated Cells ◽  
Cell Surface Biotinylation ◽  
Bait Construct ◽  
Wide Range

Large conductance Ca2+-activated K+ (BKCa) channels encoded by the Slo1 gene (also known as KCNMA1) are physiologically important in a wide range of cell types and form complexes with a number of other proteins that affect their function. We performed a yeast two-hybrid screen to identify proteins that interact with BKCa channels using a bait construct derived from domains in the extreme COOH-terminus of Slo1. A protein known as membrane-associated guanylate kinase with inverted orientation protein-1 (MAGI-1) was identified in this screen. MAGI-1 is a scaffolding protein that allows formation of complexes between certain transmembrane proteins, actin-binding proteins, and other regulatory proteins. MAGI-1 is expressed in a number of tissues, including podocytes and the brain. The interaction between MAGI-1 and BKCa channels was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays in differentiated cells of a podocyte cell line and in human embryonic kidneys (HEK)293T cells transiently coexpressing MAGI-1a and three different COOH-terminal Slo1 variants. Coexpression of MAGI-1 with Slo1 channels in HEK-293T cells results in a significant reduction in the surface expression of Slo1, as assessed by cell-surface biotinylation assays, confocal microscopy, and whole cell recordings. Partial knockdown of endogenous MAGI-1 expression by small interfering RNA (siRNA) in differentiated podocytes increased the surface expression of endogenous Slo1 as assessed by electrophysiology and cell-surface biotinylation assays, whereas overexpression of MAGI-1a reduced steady-state voltage-evoked outward current through podocyte BKCa channels. These data suggest that MAGI-1 plays a role in regulation of surface expression of BKCa channels in the kidney and possibly in other tissues.

scholarly journals Inferring Biological Mechanisms by Data-Based Mathematical Modelling: Compartment-Specific Gene Activation during Sporulation in Bacillus subtilis as a Test Case

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Dagmar Iber
Keyword(s):  
Bacillus Subtilis ◽  
Gene Activation ◽  
Experimental Information ◽  
Specific Gene ◽  
Model Parameters ◽  
Test Case ◽  
Detailed Model ◽  
Wide Range ◽  
Technical Advances ◽  
Biological Functionality

Biological functionality arises from the complex interactions of simple components. Emerging behaviour is difficult to recognize with verbal models alone, and mathematical approaches are important. Even few interacting components can give rise to a wide range of different responses, that is, sustained, transient, oscillatory, switch-like responses, depending on the values of the model parameters. A quantitative comparison of model predictions and experiments is therefore important to distinguish between competing hypotheses and to judge whether a certain regulatory behaviour is at all possible and plausible given the observed type and strengths of interactions and the speed of reactions. Here I will review a detailed model for the transcription factor , a regulator of cell differentiation during sporulation in Bacillus subtilis. I will focus in particular on the type of conclusions that can be drawn from detailed, carefully validated models of biological signaling networks. For most systems, such detailed experimental information is currently not available, but accumulating biochemical data through technical advances are likely to enable the detailed modelling of an increasing number of pathways. A major challenge will be the linking of such detailed models and their integration into a multiscale framework to enable their analysis in a larger biological context.

scholarly journals ENDOGENOUS RETROVIRUSES AS GENETIC MODULES THAT SHAPE THE GENOME REGULATORY NETWORKS DURING EVOLUTION

2018 ◽  
Keyword(s):  
Regulatory Networks ◽  
Gene Activation ◽  
Cell Types ◽  
Regulatory Elements ◽  
Endogenous Retroviruses ◽  
Protein Coding ◽  
Transcriptional Enhancers ◽  
Wide Range ◽  
Gene Regulatory Elements ◽  
Gene Regulatory

Endogenous retroviruses (ERV) are the descendants of exogenous retroviruses that integrated into the germ cells genome, fixed and became inheritable. ERVs have evolved transcriptional enhancers and promoters that allow their replication in a wide range of tissue. Because ERVs comprise the regulatory elements it could be assume that ERVs capable to shape and reshape genomic regulatory networks by inserting their promoters and enhancers in new genomic loci upon retrotransposition. Thus retroransposition events can build new regulatory regions and lead to a new pattern of gene activation in the cell. In this review we summarize evidence which revealed that ERVs provide a plethora of novel gene regulatory elements, including tissue specific promoters and enhancers for protein-coding genes or long noncoding RNAs in a wide range of cell types. The accumulated findings support the hypothesis that the ERVs have rewired the gene regulatory networks and act as a major source of genomic regulatory innovation during evolution.

scholarly journals Investigating Different DNA Methylation Patterns at the Resolution of Methylation Haplotypes

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoqing Peng ◽  
Yiming Li ◽  
Xiangyan Kong ◽  
Xiaoshu Zhu ◽  
Xiaojun Ding
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Stem Cells ◽  
Cell Types ◽  
Specific Gene ◽  
Breast Cancer Sample ◽  
Homologous Chromosomes ◽  
Differentiated Cells ◽  
Cancer Sample ◽  
Methylation Patterns

Different DNA methylation patterns presented on different tissues or cell types are considered as one of the main reasons accounting for the tissue-specific gene expressions. In recent years, many methods have been proposed to identify differentially methylated regions (DMRs) based on the mixture of methylation signals from homologous chromosomes. To investigate the possible influence of homologous chromosomes on methylation analysis, this paper proposed a method (MHap) to construct methylation haplotypes for homologous chromosomes in CpG dense regions. Through comparing the methylation consistency between homologous chromosomes in different cell types, it can be found that majority of paired methylation haplotypes derived from homologous chromosomes are consistent, while a lower methylation consistency was observed in the breast cancer sample. It also can be observed that the hypomethylation consistency of differentiated cells is higher than that of the corresponding undifferentiated stem cells. Furthermore, based on the methylation haplotypes constructed on homologous chromosomes, a method (MHap_DMR) is developed to identify DMRs between differentiated cells and the corresponding undifferentiated stem cells, or between the breast cancer sample and the normal breast sample. Through comparing the methylation haplotype modes of DMRs in two cell types, the DNA methylation changing directions of homologous chromosomes in cell differentiation and cancerization can be revealed. The code is available at: https://github.com/xqpeng/MHap_DMR.

scholarly journals Expression of muscle genes in heterokaryons depends on gene dosage.

1986 ◽  
Vol 102 (1) ◽  
pp. 124-130 ◽  
Author(s):  
G K Pavlath ◽  
H M Blau
Keyword(s):  
Gene Expression ◽  
Time Course ◽  
Gene Dosage ◽  
Cell Types ◽  
Threshold Concentration ◽  
Specific Gene ◽  
Mouse Muscle ◽  
Muscle Gene Expression ◽  
Muscle Genes ◽  
Muscle Gene

We report that gene dosage, or the ratio of nuclei from two cell types fused to form a heterokaryon, affects the time course of differentiation-specific gene expression. The rate of appearance of the human muscle antigen, 5.1H11, is significantly faster in heterokaryons with equal or near-equal numbers of mouse muscle and human fibroblast nuclei than in heterokaryons with increased numbers of nuclei from either cell type. By 4 d after fusion, a high frequency of gene expression is evident at all ratios and greater than 75% of heterokaryons express the antigen even when the nonmuscle nuclei greatly outnumber the muscle nuclei. The kinetic differences observed with different nuclear ratios suggest that the concentration of putative trans-acting factors significantly influences the rate of muscle gene expression: a threshold concentration is necessary, but an excess may be inhibitory.

scholarly journals Regulation of the CYP1A1 promoter in transgenic mice: an exquisitely sensitive on-off system for cell specific gene regulation

1996 ◽  
Vol 109 (11) ◽  
pp. 2619-2625 ◽  
Author(s):  
S.J. Campbell ◽  
F. Carlotti ◽  
P.A. Hall ◽  
A.J. Clark ◽  
C.R. Wolf
Keyword(s):  
Transgenic Mice ◽  
Transgene Expression ◽  
Expression System ◽  
Cell Types ◽  
Reproductive Organs ◽  
Specific Gene ◽  
Reporter System ◽  
Wide Range ◽  
Specific Regulation

Mammalian cytochrome P-450s in the CYP1A gene family catalyse the oxidation of a wide range of drugs and foreign compounds resulting in their excretion. These enzymes are highly inducible by a range of compounds, including polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (3-MC) and dioxins. Analysis of the CYP1A1 promoter has identified dioxin responsive enhancer elements which mediate the induction response. In order to evaluate this promoter as an in vivo regulatable expression system and to gain further insights into the tissue specific regulation of this gene, an 8.5 kb genomic fragment of the rat CYP1A1 promoter was cloned upstream of the lacZ reporter gene. This construct was used to generate transgenic mice and three independent lines were expanded for further study. The regulation of beta-galactosidase expression was determined in mock and 3-MC-treated mice in an extensive range of tissues. In untreated animals no transgene expression was detectable over non-transgenic controls. Treatment with 3-MC caused a profound increase in transgene expression (> 1,000-fold) in many tissues including liver, adrenal, kidney and intestine. Inducible transgene expression was also detectable in many of the other tissues including the spleen, lung, pancreas and the reproductive organs. Although the absolute levels of induction varied, no significant differences in the pattern of transgene expression were observed between the three different transgenic mouse lines. In addition, the pattern of transgene expression correlated closely with the reported regulation of CYP1A1 protein. These results indicate that the CYP1A1 promoter can drive expression of heterologous genes in a truly on/off manner in a variety of tissues and cell types which will allow the expression of other proteins to be controlled in vivo. This reporter system also provides a model for establishing the environmental and hormonal factors regulating the expression of the CYP1A1 gene.

scholarly journals COVID-19 genetic risk variants are associated with expression of multiple genes in diverse immune cell types

2020 ◽  
Author(s):  
Benjamin J. Schmiedel ◽  
Vivek Chandra ◽  
Job Rocha ◽  
Cristian Gonzalez-Colin ◽  
Sourya Bhattacharyya ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Immune Cell ◽  
Severe Disease ◽  
Regulatory Region ◽  
Gene Promoter ◽  
Cell Types ◽  
Risk Variants ◽  
Wide Range ◽  
Classical Monocytes ◽  
Genetic Risk Variants

ABSTRACTCommon genetic polymorphisms associated with severity of COVID-19 illness can be utilized for discovering molecular pathways and cell types driving disease pathogenesis. Here, we assessed the effects of 679 COVID-19-risk variants on gene expression in a wide-range of immune cell types. Severe COVID-19-risk variants were significantly associated with the expression of 11 protein-coding genes, and overlapped with either target gene promoter or cis-regulatory regions that interact with target promoters in the cell types where their effects are most prominent. For example, we identified that the association between variants in the 3p21.31 risk locus and the expression of CCR2 in classical monocytes is likely mediated through an active cis-regulatory region that interacted with CCR2 promoter specifically in monocytes. The expression of several other genes showed prominent genotype-dependent effects in non-classical monocytes, NK cells, B cells, or specific T cell subtypes, highlighting the potential of COVID-19 genetic risk variants to impact the function of diverse immune cell types and influence severe disease manifestations.

scholarly journals Reconstitution of Cyclin D1-Associated Kinase Activity Drives Terminally Differentiated Cells into the Cell Cycle

2001 ◽  
Vol 21 (16) ◽  
pp. 5631-5643 ◽  
Author(s):  
Lucia Latella ◽  
Alessandra Sacco ◽  
Deborah Pajalunga ◽  
Marianne Tiainen ◽  
Daniela Macera ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Cell Cycle Control ◽  
Cell Types ◽  
Dominant Negative ◽  
Specific Gene ◽  
Differentiated Cells ◽  
Highly Active

ABSTRACT Terminal cell differentiation entails definitive withdrawal from the cell cycle. Although most of the cells of an adult mammal are terminally differentiated, the molecular mechanisms preserving the postmitotic state are insufficiently understood. Terminally differentiated skeletal muscle cells, or myotubes, are a prototypic terminally differentiated system. We previously identified a mid-G1 block preventing myotubes from progressing beyond this point in the cell cycle. In this work, we set out to define the molecular basis of such a block. It is shown here that overexpression of highly active cyclin E and cdk2 in myotubes induces phosphorylation of pRb but cannot reactivate DNA synthesis, underscoring the tightness of cell cycle control in postmitotic cells. In contrast, forced expression of cyclin D1 and wild-type or dominant-negative cdk4 in myotubes restores physiological levels of cdk4 kinase activity, allowing progression through the cell cycle. Such reactivation occurs in myotubes derived from primary, as well as established, C2C12 myoblasts and is accompanied by impairment of muscle-specific gene expression. Other terminally differentiated systems as diverse as adipocytes and nerve cells are similarly reactivated. Thus, the present results indicate that the suppression of cyclin D1-associated kinase activity is of crucial importance for the maintenance of the postmitotic state in widely divergent terminally differentiated cell types.

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