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Article ; Online: Antagonistic interactions safeguard mitotic propagation of genetic and epigenetic information in zebrafish.

Lawir, Divine-Fondzenyuy / Soza-Ried, Cristian / Iwanami, Norimasa / Siamishi, Iliana / Bylund, Göran O / O Meara, Connor / Sikora, Katarzyna / Kanzler, Benoît / Johansson, Erik / Schorpp, Michael / Cauchy, Pierre / Boehm, Thomas

Communications biology

2024 Volume 7, Issue 1, Page(s) 31

Abstract: The stability of cellular phenotypes in developing organisms depends on error-free transmission of epigenetic and genetic information during mitosis. Methylation of cytosine residues in genomic DNA is a key epigenetic mark that modulates gene expression ... ...

Abstract	The stability of cellular phenotypes in developing organisms depends on error-free transmission of epigenetic and genetic information during mitosis. Methylation of cytosine residues in genomic DNA is a key epigenetic mark that modulates gene expression and prevents genome instability. Here, we report on a genetic test of the relationship between DNA replication and methylation in the context of the developing vertebrate organism instead of cell lines. Our analysis is based on the identification of hypomorphic alleles of dnmt1, encoding the DNA maintenance methylase Dnmt1, and pole1, encoding the catalytic subunit of leading-strand DNA polymerase epsilon holoenzyme (Pole). Homozygous dnmt1 mutants exhibit genome-wide DNA hypomethylation, whereas the pole1 mutation is associated with increased DNA methylation levels. In dnmt1/pole1 double-mutant zebrafish larvae, DNA methylation levels are restored to near normal values, associated with partial rescue of mutant-associated transcriptional changes and phenotypes. Hence, a balancing antagonism between DNA replication and maintenance methylation buffers against replicative errors contributing to the robustness of vertebrate development.
MeSH term(s)	Animals ; Zebrafish/genetics ; DNA Methylation ; Alleles ; DNA ; Epigenesis, Genetic
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2024-01-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-05692-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Author Correction: Antagonistic interactions safeguard mitotic propagation of genetic and epigenetic information in zebrafish.

Communications biology

2024 Volume 7, Issue 1, Page(s) 247

Language	English
Publishing date	2024-02-29
Publishing country	England
Document type	Published Erratum
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05899-y
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Article ; Online: Trimethylation and Acetylation of β-Catenin at Lysine 49 Represent Key Elements in ESC Pluripotency.

Hoffmeyer, Katrin / Junghans, Dirk / Kanzler, Benoit / Kemler, Rolf

Cell reports

2017 Volume 18, Issue 12, Page(s) 2815–2824

Abstract: Wnt/β-catenin signaling is required for embryonic stem cell (ESC) pluripotency by inducing mesodermal differentiation and inhibiting neuronal differentiation; however, how β-catenin counter-regulates these differentiation pathways is unknown. Here, we ... ...

Abstract	Wnt/β-catenin signaling is required for embryonic stem cell (ESC) pluripotency by inducing mesodermal differentiation and inhibiting neuronal differentiation; however, how β-catenin counter-regulates these differentiation pathways is unknown. Here, we show that lysine 49 (K49) of β-catenin is trimethylated (β-catMe3) by Ezh2 or acetylated (β-catAc) by Cbp. Significantly, β-catMe3 acts as a transcriptional co-repressor of the neuronal differentiation genes sox1 and sox3, whereas β-catAc acts as a transcriptional co-activator of the key mesodermal differentiation gene t-brachyury (t-bra). Furthermore, β-catMe3 and β-catAc are alternatively enriched on repressed or activated genes, respectively, during ESC and adult stem cell differentiation into neuronal or mesodermal progenitor cell lineages. Importantly, expression of a β-catenin K49A mutant results in major defects in ESC differentiation. We conclude that β-catenin K49 trimethylation and acetylation are key elements in regulating ESC pluripotency and differentiation potential.
Language	English
Publishing date	2017-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2017.02.076
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Article ; Online: p16

Grigorash, Bogdan B / van Essen, Dominic / Liang, Guixian / Grosse, Laurent / Emelyanov, Alexander / Kang, Zhixin / Korablev, Alexey / Kanzler, Benoît / Molina, Clement / Lopez, Elsa / Demidov, Oleg N / Garrido, Carmen / Liu, Feng / Saccani, Simona / Bulavin, Dmitry V

Nature cell biology

2023 Volume 25, Issue 9, Page(s) 1265–1278

Abstract: Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that ... ...

Abstract	Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16
MeSH term(s)	Animals ; Mice ; Cell Plasticity ; Cellular Reprogramming/genetics ; Aging/genetics ; Embryo Implantation ; Epigenomics
Language	English
Publishing date	2023-08-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-023-01214-9
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Article ; Online: Fundamental parameters of the developing thymic epithelium in the mouse.

Hirakawa, Mayumi / Nagakubo, Daisuke / Kanzler, Benoît / Avilov, Sergiy / Krauth, Brigitte / Happe, Christiane / Swann, Jeremy B / Nusser, Anja / Boehm, Thomas

Scientific reports

2018 Volume 8, Issue 1, Page(s) 11095

Abstract: The numbers of thymic epithelial cells (TECs) and thymocytes steadily increase during embryogenesis. To examine this dynamic, we generated several TEC-specific transgenic mouse lines, which express fluorescent proteins in the nucleus, the cytosol and in ... ...

Abstract	The numbers of thymic epithelial cells (TECs) and thymocytes steadily increase during embryogenesis. To examine this dynamic, we generated several TEC-specific transgenic mouse lines, which express fluorescent proteins in the nucleus, the cytosol and in the membranes under the control of the Foxn1 promoter. These tools enabled us to determine TEC numbers in tissue sections by confocal fluorescent microscopy, and in the intact organ by light-sheet microscopy. Compared to histological procedures, flow cytometric analysis of thymic cellularity is shown to underestimate the numbers of TECs by one order of magnitude; using enzymatic digestion of thymic tissue, the loss of cortical TECs (cTECs) is several fold greater than that of medullary TECs (mTECs), although different cTEC subsets appear to be still present in the final preparation. Novel reporter lines driven by Psmb11 and Prss16 promoters revealed the trajectory of differentiation of cTEC-like cells, and, owing to the additional facility of conditional cell ablation, allowed us to follow the recovery of such cells after their depletion during embryogenesis. Multiparametric histological analyses indicate that the new transgenic reporter lines not only reveal the unique morphologies of different TEC subsets, but are also conducive to the analysis of the complex cellular interactions in the thymus.
MeSH term(s)	Animals ; Cell Communication ; Cellular Microenvironment ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Epithelium/embryology ; Epithelium/metabolism ; Gene Expression ; Genes, Reporter ; Mice, Transgenic ; Stromal Cells/cytology ; Stromal Cells/metabolism ; Thymus Gland/embryology ; Thymus Gland/metabolism
Language	English
Publishing date	2018-07-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-29460-0
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Article ; Online: Igf1r signaling is indispensable for preimplantation development and is activated via a novel function of E-cadherin.

Bedzhov, Ivan / Liszewska, Ewa / Kanzler, Benoît / Stemmler, Marc P

PLoS genetics

2012 Volume 8, Issue 3, Page(s) e1002609

Abstract: Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal ... ...

Abstract	Insulin-like growth factor I receptor (Igf1r) signaling controls proliferation, differentiation, growth, and cell survival in many tissues; and its deregulated activity is involved in tumorigenesis. Although important during fetal growth and postnatal life, a function for the Igf pathway during preimplantation development has not been described. We show that abrogating Igf1r signaling with specific inhibitors blocks trophectoderm formation and compromises embryo survival during murine blastocyst formation. In normal embryos total Igf1r is present throughout the membrane, whereas the activated form is found exclusively at cell contact sites, colocalizing with E-cadherin. Using genetic domain switching, we show a requirement for E-cadherin to maintain proper activation of Igf1r. Embryos expressing exclusively a cadherin chimera with N-cadherin extracellular and E-cadherin intracellular domains (NcEc) fail to form a trophectoderm and cells die by apoptosis. In contrast, homozygous mutant embryos expressing a reverse-structured chimera (EcNc) show trophectoderm survival and blastocoel cavitation, indicating a crucial and non-substitutable role of the E-cadherin ectodomain for these processes. Strikingly, blastocyst formation can be rescued in homozygous NcEc embryos by restoring Igf1r signaling, which enhances cell survival. Hence, perturbation of E-cadherin extracellular integrity, independent of its cell-adhesion function, blocked Igf1r signaling and induced cell death in the trophectoderm. Our results reveal an important and yet undiscovered function of Igf1r during preimplantation development mediated by a unique physical interaction between Igf1r and E-cadherin indispensable for proper receptor activation and anti-apoptotic signaling. We provide novel insights into how ligand-dependent Igf1r activity is additionally gated to sense developmental potential in utero and into a bifunctional role of adhesion molecules in contact formation and signaling.
MeSH term(s)	Animals ; Apoptosis ; Blastocyst/cytology ; Blastocyst/metabolism ; Cadherins/genetics ; Cadherins/metabolism ; Cell Adhesion/genetics ; Cell Communication/genetics ; Cell Survival ; Embryonic Development/genetics ; Embryonic Stem Cells ; Gene Expression Regulation, Developmental ; Homozygote ; Ligands ; Mice ; Mutation ; Protein Structure, Tertiary/genetics ; Receptor, IGF Type 1/genetics ; Receptor, IGF Type 1/metabolism ; Signal Transduction/genetics
Chemical Substances	Cadherins ; Ligands ; Receptor, IGF Type 1 (EC 2.7.10.1)
Language	English
Publishing date	2012-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1002609
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Article ; Online: TT2016 meeting report on the 13th Transgenic Technology meeting in Prague, Czech Republic.

Tamowski, Susan / Luo, Jinping / Kanzler, Benoît / Whitelaw, Bruce / Crispo, Martina / Doglio, Lynn / Jerchow, Boris / Parker-Thornburg, Jan

Transgenic research

2016 Volume 25, Issue 4, Page(s) 553–559

MeSH term(s)	Czech Republic ; Gene Transfer Techniques ; Humans ; Organisms, Genetically Modified/genetics ; Organisms, Genetically Modified/growth & development
Language	English
Publishing date	2016-06-08
Publishing country	Netherlands
Document type	Congress
ZDB-ID	31620-9
ISSN	1573-9368 ; 0962-8819
ISSN (online)	1573-9368
ISSN	0962-8819
DOI	10.1007/s11248-016-9966-0
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Article: Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage

Corbeaux, Tatiana / Hess, Isabell / Swann, Jeremy B / Kanzler, Benoît / Haas-Assenbaum, Annette / Boehm, Thomas

Proceedings of the National Academy of Sciences of the United States of America. 2010 Sept. 21, v. 107, no. 38

2010

Abstract: The thymus is essential for T-cell development. Here, we focus on the role of the transcription factor Foxn1 in the development and function of thymic epithelial cells (TECs) of the mouse. TECs are of endodermal origin; they initially express Foxn1 and ... ...

Abstract	The thymus is essential for T-cell development. Here, we focus on the role of the transcription factor Foxn1 in the development and function of thymic epithelial cells (TECs) of the mouse. TECs are of endodermal origin; they initially express Foxn1 and give rise to orthotopic (thoracic) and additional (cervical) thymi. Using Foxn1-directed cytoablation, we show that during embryogenesis, cervical thymi develop a few days after the thoracic lobes, and that bipotent epithelial progenitors of cortical and medullary compartments express Foxn1. We also show that following acute selective near-total ablation during embryogenesis, complete regeneration of TECs does not occur, providing an animal model for human thymic aplasia syndromes. Finally, we address the functional role of Foxn1-negative TECs that arise postnatally in the mouse. Lineage tracing shows that such Foxn1-negative TECs are descendants of Foxn1-positive progenitors; furthermore, Foxn1-directed subacute intoxication of TECs by polyglutamine-containing EGFP proteins indicates that a presumptive Foxn1-independent lineage does not contribute to thymopoietic function of the adult thymus. Our findings therefore support the notion that Foxn1 is the essential transcription factor regulating the differentiation of TECs and that its expression marks the major functional lineage of TECs in embryonic and adult thymic tissue.
Keywords	T-lymphocytes ; abnormal development ; adults ; animal models ; embryogenesis ; epithelial cells ; epithelium ; humans ; mice ; poisoning ; proteins ; thymus gland ; transcription factors
Language	English
Dates of publication	2010-0921
Size	p. 16613-16618.
Publishing place	National Academy of Sciences
Document type	Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1004623107
Database	NAL-Catalogue (AGRICOLA)

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Article: Lentivirus as a tool for lineage-specific gene manipulations.

Malashicheva, Anna / Kanzler, Benoît / Tolkunova, Elena / Trono, Didier / Tomilin, Alexey

Genesis (New York, N.Y. : 2000)

2007 Volume 45, Issue 7, Page(s) 456–459

Abstract: The trophectoderm (TE) of blastocysts, the first epithelium established in mammalian development, (1) plays signaling, supportive, and patterning functions during preimplantation development, (2) ensures embryo implantation into the uterine wall, and (3) ...

Abstract	The trophectoderm (TE) of blastocysts, the first epithelium established in mammalian development, (1) plays signaling, supportive, and patterning functions during preimplantation development, (2) ensures embryo implantation into the uterine wall, and (3) gives rise to extraembryonic tissues essential for embryo patterning and growth after implantation. We show that mouse TE, itself permissive to lentiviral (LV) infection, represents a robust nonpermeable physical barrier to the virus particles, thereby shielding the cells of the inner cell mass from viral infection. This LV feature will allow modulations of gene expression in a lineage-specific manner, thus having significant applications in mouse functional genetics.
MeSH term(s)	Animals ; Cell Lineage ; Female ; Gene Transfer Techniques ; Genes, Reporter ; Genetic Vectors ; Lentivirus ; Male ; Mice ; Mice, Inbred C57BL
Language	English
Publishing date	2007-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2004544-X
ISSN	1526-968X ; 1526-954X
ISSN (online)	1526-968X
ISSN	1526-954X
DOI	10.1002/dvg.20313
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Article ; Online: Thymopoiesis in mice depends on a Foxn1-positive thymic epithelial cell lineage.

Corbeaux, Tatiana / Hess, Isabell / Swann, Jeremy B / Kanzler, Benoît / Haas-Assenbaum, Annette / Boehm, Thomas

Proceedings of the National Academy of Sciences of the United States of America

2010 Volume 107, Issue 38, Page(s) 16613–16618

Abstract	The thymus is essential for T-cell development. Here, we focus on the role of the transcription factor Foxn1 in the development and function of thymic epithelial cells (TECs) of the mouse. TECs are of endodermal origin; they initially express Foxn1 and give rise to orthotopic (thoracic) and additional (cervical) thymi. Using Foxn1-directed cytoablation, we show that during embryogenesis, cervical thymi develop a few days after the thoracic lobes, and that bipotent epithelial progenitors of cortical and medullary compartments express Foxn1. We also show that following acute selective near-total ablation during embryogenesis, complete regeneration of TECs does not occur, providing an animal model for human thymic aplasia syndromes. Finally, we address the functional role of Foxn1-negative TECs that arise postnatally in the mouse. Lineage tracing shows that such Foxn1-negative TECs are descendants of Foxn1-positive progenitors; furthermore, Foxn1-directed subacute intoxication of TECs by polyglutamine-containing EGFP proteins indicates that a presumptive Foxn1-independent lineage does not contribute to thymopoietic function of the adult thymus. Our findings therefore support the notion that Foxn1 is the essential transcription factor regulating the differentiation of TECs and that its expression marks the major functional lineage of TECs in embryonic and adult thymic tissue.
MeSH term(s)	Animals ; Base Sequence ; DNA Primers/genetics ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/metabolism ; Female ; Forkhead Transcription Factors/deficiency ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Gene Expression Regulation, Developmental ; Humans ; Lymphopoiesis/genetics ; Lymphopoiesis/physiology ; Mice ; Mice, Knockout ; Mice, Transgenic ; Pregnancy ; Thymus Gland/abnormalities ; Thymus Gland/cytology ; Thymus Gland/embryology ; Thymus Gland/metabolism
Chemical Substances	DNA Primers ; Forkhead Transcription Factors ; Whn protein
Language	English
Publishing date	2010-09-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1004623107
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